Substituted isoquinoline and isoquinolinone derivatives

ABSTRACT

A method for the treatment or prevention in a mammal of a disease associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase comprising administering to the mammal in need thereof at least one compound of the formula (I).

CROSS-REFERENCE

This application is a Divisional of U.S. patent application Ser. No.12/487,403 filed Jun. 18, 2009, which is a Continuation of InternationalApplication No. PCT/EP2007/011163, filed Dec. 19, 2007, which claimspriority to EP 06026898.4, filed Dec. 27, 2006, all of which areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel isoquinoline and isoquinolinonederivatives as described in the claims, their preparation and their usein the treatment and/or prevention of diseases related to the inhibitionof Rho-kinase and/or of Rho-kinase mediated phosphorylation of myosinlight chain phosphatase.

BACKGROUND OF THE INVENTION

Activation of a small GTPase RhoA upon agonist stimulation results inconversion of RhoA from the inactive GDP-bound form to the activeGTP-bound form with a subsequent binding to and activation ofRho-kinase. Two isoforms, Rho-kinase 1 and Rho-kinase 2, are known.Rho-kinase 2 is expressed in vascular smooth muscle cells andendothelial cells. Activation of Rho-kinase 2 by the active GTP-boundRhoA leads to calcium sensitization of smooth muscle cells throughphosphorylation-mediated inhibition of the myosin light chainphosphatase activity and thereby up-regulation of the activity of myosinregulatory light chain (Uehata et al., Nature 1997, 389, 990-994).

It is known that Rho-kinase is involved in vasoconstriction, includingthe development of myogenic tone and smooth muscle hypercontractility(Gokina et al. J. Appl. Physiol. 2005, 98, 1940-8), bronchial smoothmuscle contraction (Yoshii et al. Am. J. Resp. Cell Mol. Biol. 20,1190-1200), asthma (Setoguchi et al. Br J. Pharmacol. 2001, 132, 111-8;Nakahara, et al. Eur J 2000, 389,103) and chronic obstructive pulmonarydisease (COPD, Maruoka, Nippon Rinsho, 1999, 57, 1982-7), hypertension,pulmonary hypertension (Fukumoto et al. Heart, 91, 391-2, 2005, Mukai etal. Nature 1997, 389, 990-4) and ocular hypertension and regulation ofintraoccular pressure (Honjo et al. Invest. Ophthalmol. Visual Sci.2001, 42, 137-144), endothelial dysfunction (Steioff et al. Eur. J.Pharmacol. 2005, 512, 247-249), angina (Masumoto et al. Circ 2002, 105,1545-47, Shimokawa et al. JCP, 2002, 40, 751-761), nephropathy,including hypertension-induced, non-hypertension-induced, and diabeticnephropathies, renal failure and peripheral arterial occlusive disease(PAOD) (Wakino et al. Drug News Perspect. 2005, 18, 639-43), myocardialinfarction (Demiryurek et al. Eur J. Pharmacol. 2005, 527, 129-40,Hattori et al. Circulation, 2004, 109, 2234-9), cardiac hypertrophy andfailure (Yamakawa, et al. Hypertension 2000, 35, 313-318, Liao et al. AmJ Physiol Cell Physiol. 2006, 290, C661-8, Kishi et al. Circ 2005, 111,2741-2747), coronary heart disease, artherosclerosis, restenosis (Pacaudet al. Arch. Mal. Coeur 2005, 98, 249-254, Retzer, et al. FEBS Lett2000, 466, 70, Negoro, et al. Biochem Biophys Res Commun 1999, 262,211), diabetes, diabetic complications, glucose utilization andmetabolic syndrome (Sandu, et al. Diabetes 2000, 49, 2178, Maeda et al.Cell Metab. 2005, 2, 119-29), sexual dysfunction, e.g., penile erectiledysfunction (Chitaley et al. Nature Medicine 2001, 7, 119-122),retinopathy, inflammation, immune diseases, AIDS, osteoporosis,endocrine dysfunctions, e.g. hyperaldosteronism, central nervous systemdisorders such as neuronal degeneration and spinal cord injury (Nara, etal. J Neurosurg 2000, 93, 94), cerebral ischemia (Uehata, et al. Nature1997, 389, 990; Satoh et al. Life Sci. 2001, 69, 1441-53; Hitomi, et al.Life Sci 2000, 67, 1929; Yamamoto, et al. J Cardiovasc Pharmacol. 2000,35, 203-11), cerebral vasospasm (Sato, et al. Circ Res 2000, 87, 195;Kim, et al. Neurosurgery 2000, 46, 440), pain, e.g. neuropathic pain(Tatsumi, et al. Neuroscience 2005, 131, 491, Inoue, et al. Naturemedicine 2004, 10, 712), infection of digestive tracts with bacteria (WO98/06433), cancer development and progression, neoplasia whereinhibition of Rho kinase has been shown to inhibit tumor cell growth andmetastasis (Itoh, et al. Nature Medicine 1999, 5, 221; Somlyo, et al.Res Commun 2000, 269, 652), angiogenesis (Uchida, et al. Biochem BiophysRes 2000, 269, 633-40; Gingras, et al. Biochem J 2000, 348, 273),vascular smooth muscle cell proliferation and motility (Tammy et al.Circ. Res. 1999, 84, 1186-1193; Tangkijvanich et al. Atherosclerosis2001, 155, 321-327), endothelial cell proliferation, endothelial cellretraction and motility (Oikawa et al. Biochem. Biophys. Res. Commun.2000, 269, 633-640), stress fiber formation (Kimura et al. Science 1997,275, 1308-1311; Yamashiro et al. J. Cell Biol. 2000, 150, 797-806),thrombotic disorders (Kikkawa, et al. FEBS Lett. 2000, 466, 70-74; Baueret al. Blood 1999, 94, 1665-1672, Klages, et al. J Cell Biol 1999, 144,745; Retzer, et al. Cell Signal 2000, 12, 645) and leukocyte aggregation(Kawaguchi, et al. Eur J. Pharmacol. 2000, 403, 203-8; Sanchez-Madrid,et al. J. Immunol. 2003, 171, 1023-34, Sanchez-Madrid, et al. J.Immunol. 2002, 168, 400-10), and bone resorption (Chellaiah, et al. JBiol. Chem. 2003, 278, 29086-97). Na/H exchange transport systemactivation (Kawaguchi, et al. Eur J. Pharmacol. 2000, 403, 203-8),Alzheimer's disease (Zhou et al. Science 2003, 302, 1215-1217), adducinactivation (Fukata et al. J. Biol. Chem., 1998, 273, 5542-5548), and inSREB (Sterol response binding element) signalling and its effects onlipid metabolism (Lin et al. Circ. Res., 92, 1296-304, 2003).

Therefore, a compound having inhibitory effect on Rho-kinase and/or onRho-kinase mediated phosphorylation of myosin light chain phosphatase isuseful for the treatment and/or prevention of cardiovascular andnon-cardiovascular diseases involving Rho-kinase as the primary orsecondary disease cause, like hypertension, pulmonary hypertension,ocular hypertension, retinopathy, and glaucoma, peripheral circulatorydisorder, peripheral arterial occlusive disease (PAOD), coronary heartdisease, angina pectoris, heart hypertrophy, heart failure, ischemicdiseases, ischemic organ failure (end organ damage), fibroid lung,fibroid liver, liver failure, nephropathy, includinghypertension-induced, non-hypertension-induced, and diabeticnephropathies, renal failure, fibroid kidney, renal glomerulosclerosis,organ hypertrophy, asthma, chronic obstructive pulmonary disease (COPD),adult respiratory distress syndrome, thrombotic disorders, stroke,cerebral vasospasm, cerebral ischemia, pain, e.g. neuropathic pain,neuronal degeneration, spinal cord injury, Alzheimer's disease,premature birth, erectile dysfunction, endocrine dysfunctions,arteriosclerosis, prostatic hypertrophy, diabetes and complications ofdiabetes, metabolic syndrome, blood vessel restenosis, atherosclerosis,inflammation, autoimmune diseases, AIDS, osteopathy such asosteoporosis, infection of digestive tracts with bacteria, sepsis,cancer development and progression, e.g. cancers of the breast, colon,prostate, ovaries, brain and lung and their metastases.

WO 01/64238 describes isoquinoline-5-sulfonamide derivatives optionallysubstituted by a —(CH₂)₁₋₆—O—(CH₂)₀₋₆—, a —(CH₂)₀₋₆—S—(CH₂)₀₋₆- or a—(CH₂)₀₋₆-linked heterocyclic group useful as neuroprotective agents.

WO 2004/106325 (Schering AG) describes prodrugs of the Rho-kinaseinhibitor fasudil carrying an ether or ester group in the 1-position ofthe isoquinoline ring.

WO 2001/039726 generically describes —O—(C₀-C₁₀)alkyl-heteroarylsubstituted cyclohexyl derivatives useful for the treatment of microbialinfections. JP 10087629 A describes isoquinoline derivatives useful forthe treatment of diseases caused by Heliobacter pylori such as forexample gastritis cancer or ulcer. The isoquinoline derivatives may besubstituted by OH in the 1-position and are preferably 5-substituted byX—[(C₁-C₆)alkylene)]₀₋₁—Y wherein X may be oxygen and Y may be an arylor a heterocyclic group.

Hagihara et al. (Bioorg. Med. Chem. 1999, 7, 2647-2666) disclose6-benzyloxy-isoquinoline for the treatment of infections caused byHeliobacter pylori.

U.S. Pat. No. 5,480,883 generically discloses as EGF and/or PDGFreceptor inhibitors useful for inhibiting cell proliferation compoundsof the formula “Ar I—X—Ar II” wherein X may be (CHR₁)_(m)—Z—(CHR₁)_(n),e.g. Z—CH₂, wherein Z may be O, R₁ is hydrogen or alkyl, Ar I may beamong others an optionally substituted isoquinolone and Ar II may beamong others an optionally substituted C₃₋₇ monocyclic saturatedheterocyclic system.

WO 2005/030791 (Merck & Co.) generically describes as potassium channelinhibitors for the treatment of cardiac arrhythmias, stroke, congestiveheart failure etc. isoquinolone derivatives which are optionallysubstituted in 6-position by a group (CR^(e)R^(f))_(p)OR⁴³ wherein p maybe zero, and R⁴³ is e.g. a (C₃-C₁₀)cycloalkyl residue optionallysubstituted by NR⁵¹R⁵², wherein R⁵¹ and R⁵² may be hydrogen,(C₁-C₆)alkyl etc.; or R⁴³ is a group R⁸¹ defined as a 4-6 memberedunsaturated or saturated monocyclic heterocylic ring with 1, 2, 3 or 4heteroatoms; and are substituted by a directly bound optionallysubstituted aryl or heteroaryl ring in the 4-position.

WO 2005/030130 (Merck & Co.) generically describes as potassium channelinhibitors for the treatment of cardiac arrhythmias, stroke, congestiveheart failure etc. isoquinoline derivatives which may be substituted byhydroxyl in the 1-position and are optionally substituted in 6-positionby a group (CR^(e)R^(f))_(p)OR⁴³ wherein p may be zero, and R⁴³ is e.g.a (C₃-C₁₀)cycloalkyl residue optionally substituted by NR⁵¹R⁵², whereinR⁵¹ and R⁵² may be hydrogen, (C₁-C₆)alkyl etc.; or R⁴³ is a group R⁸¹defined as a 4-6 membered unsaturated or saturated monocyclicheterocylic ring with 1, 2, 3 or 4 heteroatoms; and are substituted by adirectly bound optionally substituted aryl or heteroaryl ring in the4-position.

WO 03/053330 (Ube) generically describes isoquinolone derivatives of theformula

as Rho-kinase inhibitors.

WO 00/24718 (Akzo) describes inter alia 1-amino-isoquinoline derivativesfor use as serine protease inhibitors which are substituted in the 6position with a group —O—(CH2)m-E-D-J wherein m is one or two and E, D,J are as defined in the application.

EP-A-1 541 559 (Asahi) generically describes isoquinoline andisoquinolone derivatives substituted in the 5-position by a group R3 asRho-kinase inhibitors.

SUMMARY OF THE INVENTION

An embodiment of the present invention is a compound of the formula (I)

whereinR₁ is H, OH or NH₂;R₂ is hydrogen, halogen or (C₁-C₆)alkyl;R₃ isH,halogen,(C₁-C₆)alkyl,(C₁-C₆)alkylene-R′,OH,O—R″,NH₂,NHR″,NR″R″ orNH—C(O)—R″,R₄ isH,halogen,hydroxy,CN,(C₁-C₆)alkyl,R′,(C₁-C₆)alkylene-R′;R₅ isH,halogen,CN,NO₂,(C₁-C₆)alkyl,(C₂-C₆)alkenyl,R′,(C₁-C₆)alkylene-(C₆-C₁₀)aryl,(C₁-C₆)alkenylene-(C₆-C₁₀)aryl,(C₁-C₆)alkylene-(C₅-C₁₀)heterocyclyl,CH(OH)—(C₁-C₆)alkyl,NH₂,NH—R′,NH—SO₂H,NH—SO₂—(C₁-C₆)alkyl,NH—SO₂—R′,NH—C(O)—(C₁-C₆)alkyl,NH—C(O)—R′,C(O)N[(C₁-C₆)alkyl]₂,C(O)OH, orC(O)O—(C₁-C₆)alkyl;R₆ isH,R′,(C₁-C₈)alkyl,(C₁-C₆)alkylene-R′,(C₁-C₆)alkylene-O—(C₁-C₆)alkyl,(C₁-C₆)alkylene-O—R′,(C₁-C₆)alkylene-CH[R′]₂,(C₁-C₆)alkylene-C(O)—R′,(C₁-C₆)alkylene-C(O)NH₂,(C₁-C₆)alkylene-C(O)NH—R′,(C₁-C₆)alkylene-C(O)NH—(C₁-C₆)alkyl,(C₁-C₆)alkylene-C(O)N[(C₁-C₆)alkyl]₂,(C₁-C₆)alkylene-C(O)N[R′]₂;(C₁-C₆)alkylene-C(O)O—(C₁-C₆)alkyl,C(O)O—(C₁-C₆)alkyl,C(O)OR′C(O)(C₁-C₆)alkyl,C(O)R′,C(O)NH—(C₁-C₆)alkyl,C(O)NHR′,C(O)N[(C₁-C₆)alkyl]R′C(O)N[(C₁-C₆)alkyl]₂,C(O)—(C₁-C₆)alkylene-R′, orC(O)O(C₁-C₆)alkylene-R′;R₇ isH,halogen,CN,NO₂,(C₁-C₆)alkyl,O—(C₁-C₆)alkyl,(C₂-C₆)alkenyl,R′,(C₁-C₆)alkenylene-(C₆-C₁₀)aryl,(C₁-C₆)alkylene-R′,CH(OH)—(C₁-C₆)alkyl,NH₂,NH—R′,NH—SO₂H,NH—SO₂—(C₁-C₆)alkyl,NH—SO₂—R′,SO₂—NH₂,SO₂—NHR′,NH—C(O)—(C₁-C₆)alkyl,NH—C(O)—R′,C(O)N[(C₁-C₆)alkyl]₂,C(O)OH, orC(O)O—(C₁-C₆)alkyl;R₈ is H, halogen or (C₁-C₆)alkyl;n is 1, 2, 3 or 4;m is 1, 2, 3, 4 or 5; andL is O or O—(C₁-C₆)alkylene;whereinR′ is(C₃-C₈)cycloalkyl,(C₅-C₁₀)heterocyclyl,(C₆-C₁₀)aryl;R″ is(C₃-C₈)cycloalkyl,(C₅-C₁₀)heterocyclyl,(C₆-C₁₀)aryl,(C₁-C₆)alkyl,(C₁-C₆)alkylene-R′,(C₁-C₆)alkylene-O—(C₁-C₆)alkyl,(C₁-C₆)alkylene-O—R′, or(C₁-C₆)alkylene-NR_(x)R_(y); andwherein R_(x) and R_(y) are independently of each other(C₁-C₆)alkyl,(C₅-C₁₀)heterocyclyl,(C₆-C₁₀)aryl,(C₁-C₄)alkylene-(C₅-C₁₀)heterocyclyl,(C₁-C₄)alkylene-(C₆-C₁₀)aryl,(C₁-C₄)alkylene-NH(C₁-C₆)alkyl,(C₁-C₄)alkylene-N[(C₁-C₆)alkyl]₂,(C₁-C₄)alkylene-N[(C₆-C₁₀)aryl]₂, or

(C₁-C₄)alkylene-N[(C₅-C₁₀)heterocyclyl]₂;

wherein in residues R₄, R₅, R₆, R₇ and R₈ alkyl, alkylene or cycloalkylcan optionally be substituted one or more times by OH, OCH₃, COOH,COOCH₃, NH₂, NHCH₃, N(CH₃)₂, CONHCH₃ or CON(CH₃)₂;

wherein in residues R₂ to R₈ alkyl or alkylene can optionally besubstituted one or more times by halogen;

wherein in residues R₃ to R₈ (C₆-C₁₀)aryl and (C₅-C₁₀)heterocyclyl areunsubstituted or substituted one or more times by suitable groupsindependently selected from halogen, OH, NO₂, N₃, CN, C(O)—(C₁-C₆)alkyl,C(O)—(C₁-C₆)aryl, COOH, COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₆)alkyl,CON[(C₁-C₆)alkyl]₂, (C₃-C₈)cycloalkyl, (C₁-C₆)alkyl, (C₁-C₆)alkylene-OH,(C₁-C₆)alkylene-NH₂, (C₁-C₆)alkylene-NH(C₁-C₆)alkyl,(C₁-C₆)alkylene-N[(C₁-C₆)alkyl]₂, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,O—(C₁-C₆)alkyl, O—C(O)—(C₁-C₆)alkyl, PO₃H₂, SO₃H, SO₂—NH₂,SO₂NH(C₁-C₆)alkyl, SO₂N[(C₁-C₆)alkyl]₂, S—(C₁-C₆)alkyl, SO—(C₁-C₆)alkyl,SO₂—(C₁-C₆)alkyl, SO₂—N═CH—N[(C₁-C₆)alkyl]₂,C(NH)(NH₂), NH₂, NH—(C₁-C₆)alkyl, N[(C₁-C₆)alkyl]₂,NH—C(O)—(C₁-C₆)alkyl, NH—C(O)O—(C₁-C₆)alkyl,NH—SO₂—(C₁-C₆)alkyl, NH—SO₂—(C₆-C₁₀)aryl, NH—SO₂—(C₅-C₁₀)heterocyclyl,N(C₁-C₆)alkyl-C(O)—(C₁-C₆)alkyl, N(C₁-C₆)alkyl-C(O)O—(C₁-C₆)alkyl,N(C₁-C₆)alkyl-C(O)—NH—(C₁-C₆)alkyl],(C₆-C₁₀)aryl, (C₁-C₆)alkylene-(C₆-C₁₀)aryl, O—(C₆-C₁₀)aryl,O—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, (C₅-C₁₀)heterocyclyl,(C₁-C₆)alkylene-(C₆-C₁₀)heterocyclyl, orO—(C₁-C₆)alkylene-(C₆-C₁₀)heterocyclyl, wherein the (C₆-C₁₀)aryl or(C₅-C₁₀)heterocyclyl may be substituted one to three times by a groupindependently selected from halogen, OH, NO₂, CN, O—(C₁-C₆)alkyl,(C₁-C₆)alkyl, NH₂, NH(C₁-C₆)alkyl, N[(C₁-C₆)alkyl]₂, SO₂CH₃, COOH,C(O)O—(C₁-C₆)alkyl, CONH₂, (C₁-C₆)alkylene-O—(C₁-C₆)alkyl,(C₁-C₆)alkylene-O—(C₆-C₁₀)aryl, or O—(C₁-C₆)alkylene-(C₆-C₁₀)aryl;or wherein (C₆-C₁₀)aryl is vicinally substituted by aO—(C₁-C₄)alkylene-0 group whereby a 5-8-membered ring is formed togetherwith the carbon atoms the oxygen atoms are attached to;and wherein aryl or heterocyclyl substituents of (C₆-C₁₀)aryl and(C₅-C₁₀)heterocyclyl groups may not be further substituted by an aryl orheterocyclyl containing group;and wherein, if m is 3, R₆ is not H, (C₅-C₁₀)heterocyclyl or(C₆-C₁₀)aryl; andwherein, if m is 3 and R₆ is a residue selected from(C₁-C₈)alkyl,(C₃-C₈)cycloalkyl,(C₁-C₆)alkylene-R′,(C₁-C₆)alkylene-O—(C₁-C₆)alkyl,(C₁-C₆)alkylene-O—R′,(C₁-C₆)alkylene-CH[R′]₂,(C₁-C₆)alkylene-C(O)—R′,(C₁-C₆)alkylene-C(O)NH₂,(C₁-C₆)alkylene-C(O)NH—R′, or(C₁-C₆)alkylene-C(O)N[R′]₂;alkyl, alkylene or cycloalkyl in said residue is substituted one or moretimes, preferably one to three times, by OH, OCH₃, COOH, COOCH₃, NH₂,NHCH₃, N(CH₃)₂, CONHCH₃ or CON(CH₃)₂;or their stereoisomeric forms and/or their tautomeric forms and/or theirpharmaceutically acceptable salts.

DETAILED DESCRIPTION OF THE INVENTION Definitions

In a preferred embodiment of the present invention R₁ is H, the compoundis thus characterized by the formula (II)

In another embodiment R₁ is OH, the compound is thus characterized bythe formula

The compound of formula (III) has a tautomeric form of the formula(III′)

The tautomeric form is also an embodiment of the present invention.

In a further embodiment R₁ is NH₂ and the compound has the formula (IV)

R₁ is preferably H or OH.

R₃ is preferably H, halogen, (C₁-C₄)alkylene-R′, O—R″ or NHR″. Morepreferred, R₃ is H or NHR″. Most preferred, R₃ is H,NH—(C₅-C₆)heterocyclyl or NH-phenyl, especially preferred are H,NH—(C₅-C₆)heteroaryl containing one or more N atoms or NH-phenyl. Mostespecially preferred, R₃ is H.

Examples of R₃ substituents are

Preferably, R₄ is H, halogen or (C₁-C₆)alkyl. More preferred, R₄ is H,halogen or (C₁-C₄)alkyl. Most preferred, R₄ is H.

Preferably, R₅ is H, halogen, CN, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, R′,NH—(C₆-C₁₀)aryl or (C₁-C₆)alkylene-R′. More preferably, R₅ is H,halogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, R′, NH—(C₆-C₁₀)aryl or(C₁-C₆)alkylene-R′. Most preferably, R₅ is H, halogen, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₆-C₁₀)aryl, NH—(C₆-C₁₀)aryl, (C₁-C₂)alkyl-(C₆-C₁₀)arylor (C₅-C₁₀)heteroaryl. Especially preferred, R₅ is H, halogen, phenyl,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₆-C₁₀)aryl or (C₅-C₆)heteroaryl. Mostespecially preferred R₅ is H, halogen, methyl, ethyl, vinyl, phenyl,thienyl or pyridyl.

Examples of R₅ are hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl,vinyl, phenyl, thienyl or pyridyl, nitrile, nitro, (p-methoxy)-phenyl,N-aniline, benzyl, 2-propenyl, s-butenyl, cyclopropyl, tetrazol, amino,4-methoxy-aniline or N-acetyl, preferably hydrogen, fluoro, chloro,bromo, iodo, methyl, ethyl, vinyl, phenyl, thienyl or pyridyl. Morepreferred, R₅ is H, halogen, methyl, or ethyl, most preferred R₅ is H.

Preferably, R₆ is H, (C₁-C₆)alkyl, R′, (C₁-C₄)alkylene-(C₅-C₁₀)aryl,(C₁-C₄)alkylene-(C₃-C₈)cycloalkyl, (C₁-C₄)alkylene-(C₅-C₁₀)heterocyclyl,(C₁-C₆)alkylene-O—(C₁-C₆)alkyl,(C₁-C₄)alkylene-C(O)—(C₅-C₁₀)heterocyclyl,(C₁-C₄)alkylene-C(O)—(C₆-C₁₀)aryl, (C₁-C₆)alkylene-C(O)N[(C₁-C₆)alkyl]₂,(C₁-C₆)alkylene-C(O)NH—(C₁-C₆)alkyl, (C₁-C₆)alkylene-C(O)O—(C₁-C₆)alkyl,C(O)O—(C₁-C₆)alkyl, C(O)(C₁-C₆)alkyl, C(O)R′, C(O)NH—(C₁-C₆)alkyl,C(O)N[(C₁-C₆)alkyl]₂, or C(O)(C₁-C₆)alkylene-R′.

In a further preferred embodiment R₆ is H, (C₁-C₆)alkyl,(C₅-C₁₀)heterocyclyl, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl,(C₁-C₄)alkylene-(C₃-C₈)cycloalkyl, (C₁-C₄)alkylene-(C₅-C₁₀)heterocyclyl,(C₁-C₄)alkylene-(C₆-C₁₀)aryl, (C₁-C₆)alkylene-O—(C₁-C₆)alkyl,(C₁-C₆)alkylene-C(O)N[(C₁-C₆)alkyl]₂,(C₁-C₆)alkylene-C(O)NH—(C₁-C₆)alkyl, (C₁-C₆)alkylene-C(O)O—(C₁-C₆)alkyl,C(O)O—(C₁-C₆)alkyl, C(O)(C₁-C₆)alkyl, C(O)—(C₅-C₁₀)heterocyclyl,C(O)(C₃-C₈)cycloalkyl, C(O)NH—(C₁-C₆)alkyl, C(O)N[(C₁-C₆)alkyl]₂, C(O)(C₁-C₆)alkylene-(C₃-C₈)cycloalkyl, C(O)(C₁-C₆)alkylene-C₅-C₁₀)heterocyclyl, orC(O)(C₁-C₆)alkylene-(C₆-C₁₀)aryl:

In a further more preferred embodiment R₆ is H, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₅-C₁₀)heterocyclyl, (C₅-C₁₀)aryl,(C₁-C₄)alkylene-(C₃-C₈)cycloalkyl, (C₁-C₄)alkylene-(C₅-C₁₀)heterocyclyl,(C₁-C₄)alkylene-(C₆-C₁₀)aryl, (C₁-C₆)alkylene-O—(C₁-C₆)alkyl,(C₁-C₆)alkylene-C(O)NH—(C₁-C₆)alkyl,(C₁-C₆)alkylene-C(O)N[(C₁-C₆)alkyl]₂, C(O)O—(C₁-C₆)alkyl,C(O)(C₁-C₆)alkyl, C(O)(C₃-C₈)cycloalkyl, C(O)—(C₅-C₁₀)heterocyclyl,C(O)NH—(C₁-C₆)alkyl, C(O)N[(C₁-C₆)alkyl]₂,C(O)(C₁-C₆)alkylene-(C₃-C₈)cycloalkyl,C(O)(C₁-C₆)alkylene-(C₅-C₁₀)heterocyclyl, orC(O)(C₁-C₆)alkylene-(C₆-C₁₀)aryl.

In an more preferred embodiment R₆ is H, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, (C₁-C₄)alkylene-(C₃-C₈)cycloalkyl,(C₁-C₄)alkylene-(C₅-C₁₀)heterocyclyl, (C₁-C₄)alkylene-(C₆-C₁₀)aryl,(C₁-C₄)alkylene-O—(C₁-C₄)alkyl, C(O)(C₁-C₆)alkyl, C(O)(C₃-C₈)cycloalkyl,C(O)—(C₅-C₁₀)heterocyclyl, C(O)(C₁-C₄)alkylene-(C₅-C₁₀)heterocyclyl, orC(O)(C₁-C₄)alkylene-(C₆-C₁₀)aryl.

In an even more preferred embodiment R₆ is

H,

(C₁-C₆)alkyl,

(C₃-C₈)cycloalkyl;

(C₁-C₄)alkylene-(C₃-C₈)cycloalkyl;

(C₁-C₄)alkylene-(C₅-C₁₀)heterocyclyl wherein heterocyclyl isunsubstituted or substituted one or more times, preferably one or twotimes, by (C₁-C₄)alkyl;

(C₁-C₄)alkylene-(C₆-C₁₀)aryl wherein aryl is unsubstituted orsubstituted one or more times, preferably one to three times, byhalogen, (C₁-C₄)alkyl especially CH₃ or CF₃, O—(C₁-C₄)alkyl especiallyOCH₃, SO₂—(C₁-C₄)alkyl especially S(O)₂CH₃ or SO₂CF₃, orSO₂—N═CH—N[(C₁-C₆)alkyl]₂ especially SO₂—N═CH—N(CH₃)₂;C(O)(C₁-C₆)alkyl, preferably C(O)(C₁-C₄)alkyl,C(O)(C₃-C₆)cycloalkyl,C(O)—(C₅-C₆)heterocyclyl wherein the heterocyclyl is unsubstituted;C(O)(C₁-C₄)alkylene-(C₅-C₁₀)heterocyclyl wherein the heterocyclyl isunsubstituted; orC(O)(C₁-C₄)alkylene-(C₆-C₁₀)aryl wherein the aryl is unsubstituted orsubstituted one or more times, preferably one to three times, byhalogen;whereina (C₁-C₄)alkyl or (C₁-C₆)alkyl residue is unsubstituted or substitutedone to three times, preferably one or two times, by a groupindependently selected from OH, halogen, NH₂, NH(CH₃) or N(CH₃)₂,a (C₁-C₄)alkylene residue is unsubstituted or substituted once by aminoor N(CH₃)₂ and a (C₃-C₈)cycloalkyl residue is unsubstituted orsubstituted once by NH₂.

In another especially preferred embodiment R6 is

(C₁-C₆)alkylene-C(O)NH₂,

(C₁-C₆)alkylene-C(O)NH—(C₁-C₆)alkyl,

(C₁-C₆)alkylene-C(O)N[(C₁-C₆)alkyl]₂,

C(O)(C₁-C₆)alkyl, preferably C(O)(C₁-C₄)alkyl,

C(O)(C₃-C₆)cycloalkyl, wherein the cycloalkyl is unsubstituted orsubstituted once by NH₂,

C(O)—(C₅-C₆)heterocyclyl wherein the heterocyclyl is unsubstituted;

C(O)(C₁-C₄)alkylene-(C₅-C₁₀)heterocyclyl wherein the heterocyclyl isunsubstituted;

C(O)(C₁-C₄)alkylene-(C₆-C₁₀)aryl wherein the aryl is unsubstituted orsubstituted one or more times, preferably one to three times, byhalogen;

wherein

a (C₁-C₄)alkyl or (C₁-C₆)alkyl residue is unsubstituted or substitutedone to three times, preferably one or two times, by a groupindependently selected from OH, halogen, NH₂, NH(CH₃) or N(CH₃)₂,

a (C₁-C₄)alkylene residue is unsubstituted or substituted once by amino,NH(CH₃) or N(CH₃)₂; or is

(C₁-C₆)alkyl, wherein alkyl is substituted once with amino.

More preferred R6 is

C(O)(C₁-C₆)alkyl, preferably C(O)(C₁-C₄)alkyl,

wherein the alkyl is unsubstituted or, preferably, substituted one tothree times, preferably one or two times, most preferably once, by agroup independently selected from OH, halogen, NH₂, NH(CH₃) or N(CH₃)₂;

C(O)—(C₅-C₆)heterocyclyl wherein the heterocyclyl is unsubstituted;

C(O)—(C₃-C₆)cycloalkyl, wherein cycloalkyl is unsubstituted orsubstituted by amino, or

C(O)(C₁-C₄)alkylene-(C₆-C₁₀)aryl wherein the aryl is phenyl which isunsubstituted or substituted one or more times, preferably one to threetimes, more preferably once, by halogen and wherein the alkylene isunsubstituted or, preferably, substituted once by amino, NH(CH₃) orN(CH₃)₂.

Especially preferred R₆ is H, (C₁-C₆)alkyl or (C₃-C₈)cycloalkyl. In aneven more especially preferred embodiment R₆ is H, preferablyunsubstituted (C₁-C₆)alkyl or preferably unsubstituted(C₃-C₈)cycloalkyl. Most preferred R₆ is H.

In a embodiment of a compound of formula (I) R₆ is nottert-butyloxycarbonyl.

As examples for these embodiments, R₆ is hydrogen, methyl, ethyl,propyl, isopropyl, 3-methyl-butyl, 2-methyl-propyl, butyl, pentyl,3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl or a substituent selectedfrom the group consisting of

Other R6 examples are

The asterisk (*) denotes where the bond is connected to the N-atom ofthe ring.

Preferably, R₇ is H, halogen, CN, (C₁-C₈)alkyl, O—(C₁-C₈)alkyl,(C₂-C₈)alkenyl, R′ or (C₁-C₈)alkylene-(C₃-C₈)cycloalkyl. More preferred,R₇ is H, halogen, CN, (C₁-C₄)alkyl, O—(C₁-C₄)alkyl, (C₁-C₄)alkenyl,phenyl, cyclopropyl or (C₅-C₈)heteroaryl. Most preferably, R₇ is H,fluoro, chloro, bromo, methyl, ethyl, methoxy, propyl, phenyl, nitrile,cyclopropyl, thienyl or vinyl, most especially preferred R₇ is H,fluoro, chloro, bromo, methyl, propyl or methoxy. Most preferred R₇ isH.

R₈ is preferably H, halogen or (C₁-C₄)alkyl. More preferred, R₈ is H,Cl, F, methyl or ethyl. Most preferred R₈ is H.

Preferably, R₂ is H, halogen or (C₁-C₄)alkyl. Preferably, R₂ is H or(C₁-C₂)alkyl. More preferred, R₂ is H, methyl or ethyl. Most preferredR₂ is H. R₂ may be bound to any carbon atom of the ring including theposition where the linker group L is bound.

Preferably, n is 1, 2 or 3. More preferred, n is 1 or 2. Most preferredn is 1.

Preferably m is 2, 3 or 4. More preferred m is 3. In another embodimentm is 1, 2, 4 or 5.

The linker group L may be bound to the ring in any position via a ringcarbon atom. In a preferred embodiment, m is 3 and L is attached to the4-position of the piperidine ring

or L is attached to the 3-position of the piperidine ring

In an especially preferred embodiment, L is attached to the 4-positionof the piperidine ring.

In a further preferred embodiment, L is O-methylene, O-ethylene orpreferably O. In another preferred embodiment L is O-methylene or O.More preferably, m is 3 and L is O-methylene, O-ethylene or O attachedto the 4-position of the piperidine ring.

In residues R₂ to R₈ an alkyl or alkylene can optionally be substitutedone or more times by halogen. Preferably alkyl or alkylene issubstituted one to three times by halogen selected from chloro or bromobut may be substituted by fluoro once or more, e.g. beingperfluorinated. Preferably halogen is Fluor. More preferred an alkyl oralkylene is not halogenated.

In residues R₄, R₅, R₆, R₇ and R₈ alkyl, alkylene or cycloalkyl canoptionally be substituted one or more times by a group selectedindependently from OH, OCH₃, COOH, COOCH₃, NH₂, NHCH₃, N(CH₃)₂, CONHCH₃or CON(CH₃)₂.

If substituted, the number of substituents is preferably between 1, 2, 3or 4, more preferably 1 or 2 with 1 being even more preferred.Preferably an alkylene or cycloalkyl is not substituted. More preferablyan alkyl, alkylene or cycloalkyl is not substituted. Preferably in R₄,R₅, R₇ and R₈ an alkyl, alkylene or cycloalkyl is not substituted. Morepreferred, in R₄, R₅, R₆, R₇ and R₈ an alkyl, alkylene or cycloalkyl isnot substituted.

In preferred embodiments of the present invention one or more or all ofthe groups contained in the compounds of formula (I) can independentlyof each other have any of the preferred, more preferred or mostpreferred definitions of the groups specified above or any one or someof the specific denotations which are comprised by the definitions ofthe groups and specified above, all combinations of preferreddefinitions, more preferred or most preferred and/or specificdenotations being a subject of the present invention. Also with respectto all preferred embodiments the invention includes the compounds of theformula (I) in all stereoisomeric forms and mixtures of stereoisomericforms in all ratios, and their pharmaceutically acceptable salts.

The term “*-” in the exemplified substituents vide supra marks the pointwhere the substituent is attached, which means, for example, for a R₃substituent

and m is 3 and R1 is H a compound of the formula

A preferred embodiment is a compound of the formula (I) wherein

R₁ is H or OH;

R₂ is hydrogen, halogen, or (C₁-C₆)alkyl;

R₃ is H, halogen, (C₁-C₄)alkylene-R′, O—R″ or NHR″;

R₄ is H, halogen or (C₁-C₆)alkyl;

R₅ is H, (C₁-C₆)alkyl, halogen, CN, (C₂-C₆)alkenyl, (C₆-C₁₀)aryl,NH—(C₆-C₁₀)aryl, (C₁-C₆)alkylene-(C₆-C₁₀)aryl, (C₅-C₁₀)heterocyclyl or

(C₁-C₆)alkylene-(C₅-C₁₀)heterocyclyl;

R₆ is H, R′, (C₁-C₈)alkyl, (C₁-C₆)alkylene-R′,(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, (C₁-C₆)alkylene-O—R′,(C₁-C₆)alkylene-CH[R′]₂, (C₁-C₆)alkylene-C(O)NH₂,(C₁-C₆)alkylene-C(O)NH—R′, (C₁-C₆)alkylene-C(O)N[(C₁-C₄)alkyl]₂,C(O)(C₁-C₄)alkyl or (C₁-C₆)alkylene-C(O)N[R′]₂,C(O)O—(C₁-C₆)alkyl, C(O)(C₁-C₆)alkyl, C(O)(C₃-C₈)cycloalkyl,C(O)NH—(C₁-C₆)alkyl, C(O)N[(C₁-C₆)alkyl]₂,C(O)(C₁-C₆)alkylene-C₃-C₈)cycloalkyl, C(O)(C₁-C₆)alkylene-C₅-C₁₀)heterocyclyl or C(O)(C₁-C₆)alkylene-(C₆-C₁₀)aryl.R₇ is H, halogen, CN, (C₁-C₆)alkyl, O—(C₁-C₆)alkyl, (C₂-C₆)alkenyl orR′;R₈ is H, halogen or (C₁-C₆)alkyl;m is 2, 3 or 4n is 1, 2 or 3, andL is O,O-methylene or O-ethylene;or their stereoisomeric and/or tautomeric forms and/or theirpharmaceutically acceptable salts.

A further preferred embodiment is a compound of the formula (I) wherein

R₁ is H or OH;

R₂ is H or (C₁-C₄)alkyl;

R₃ is H, halogen or NHR″, wherein R″ is defined as above;

R₄ is H, halogen or (C₁-C₄)alkyl;

R₅ is H, (C₁-C₆)alkyl, halogen, (C₂-C₄)alkenyl, (C₆-C₁₀)aryl,(C₁-C₆)alkylene-(C₆-C₁₀)aryl or (C₅-C₁₀)heterocyclyl;

R₆ is H, (C₃-C₈)cycloalkyl, (C₁-C₈)alkyl,(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, (C₁-C₃)alkylene-R′, C(O)O—(C₁-C₆)alkyl,C(O)(C₁-C₆)alkyl, C(O)(C₃-C₈)cycloalkyl, C(O)—(C₅-C₁₀)heterocyclyl,C(O)NH—(C₁-C₆)alkyl, C(O)N [(C₁-C₆)alkyl]₂,

C(O)(C₁-C₃)alkylene-(C₃-C₈)cycloalkyl,C(O)(C₁-C₃)alkylene-(C₅-C₁₀)heterocyclyl, orC(O)(C₁-C₃)alkylene-(C₆-C₁₀)aryl;

R₇ is H, halogen, CN, (C₁-C₆)alkyl, O(C₁-C₆)alkyl, (C₂-C₆)alkenyl or R′;

R₈ is H, halogen or (C₁-C₆)alkyl;

m is 2, 3 or 4

n is 1, 2 or 3; and

L is O;

or their stereoisomeric and/or tautomeric forms and/or theirpharmaceutically acceptable salts.

An especially preferred embodiment is a compound of the formula (I)wherein

R₁ is H or OH;

R₂ is H, (C₁-C₄)alkyl;

R₃ is H, NH—(C₅-C₆)heteroaryl or NH-phenyl;

R₄ is H, halogen or (C₁-C₄)alkyl;

R₅ is H, (C₁-C₄)alkyl, halogen, (C₁-C₄)alkenyl, (C₆-C₁₀)aryl,(C₁-C₂)alkyl-(C₆-C₁₀)aryl or (C₅-C₆)heteroaryl;

R₆ is H, (C₃-C₈)cycloalkyl, (C₁-C₈)alkyl, (C₁-C₃)alkylene-R′;C(O)(C₁-C₆)alkyl, C(O)(C₃-C₈)cycloalkyl, C(O)—(C₅-C₁₀)heterocyclyl,C(O)(C₁-C₃)alkylene-(C₅-C₁₀)heterocyclyl, orC(O)(C₁-C₃)alkylene-(C₆-C₁₀)aryl.

R₇ is H, halogen, CN, (C₁-C₄)alkyl, O(C₁-C₄)alkyl, (C₁-C₄)alkenyl,phenyl, cyclopropyl, (C₅-C₆)heteroaryl;

R₈ is H, halogen or (C₁-C₄)alkyl;

m is 3

n is 1; and

L is O;

or their stereoisomeric and/or tautomeric forms and/or theirpharmaceutically acceptable salts.

In a embodiment a compound of formula (I) is not(2S)-1-tert-butoxycarbonyl-2-(2-(1-amino-isoquinolin-6-oxy)ethyl)-piperidineor(2S)-1-tert-butoxycarbonyl-2-(2-(1-amino-isoquinolin-6-oxy)ethyl)-pyrrolidine.

In another embodiment of a compound of formula (I) wherein

R1 is NH₂ or OH; R3 and R8 are H; R4 is H when R1 is NH₂ or R4 is H orbromo when R1 is OH; R5 is H; R7 is H or methyl; m is 2, 3, or 4; L isO;

R6 is not H, pyrrolyl, methyl, hydroxypropyl, or phenylmethyl whereinthe phenyl group is unsubstituted or substituted by methanesulfonyl,methyl, fluoro, or methoxy.

In a further embodiment, the present invention relates to a compound offormula (I) selected from

-   8.    7-Chloro-6-[1-(2-methylamino-acetyl)-piperidin-4-yloxy]-2H-isoquinolin-1-one,-   10.    6-[1-(2-Amino-3,3-dimethyl-butyryl)-piperidin-4-yloxy]-7-chloro-2H-isoquinolin-1-one,-   11.    6-[1-(2-Amino-propionyl)-piperidin-4-yloxy]-7-chloro-2H-isoquinolin-1-one,-   12.    6-[1-(2-Amino-2-methyl-propionyl)-piperidin-4-yloxy]-7-chloro-2H-isoquinolin-1-one-   13.    6-[1-((S)-2-Amino-butyryl)-piperidin-4-yloxy]-7-chloro-2H-isoquinolin-1-one,-   14.    6-[1-((S)-2-Amino-4-methyl-pentanoyl)-piperidin-4-yloxy]-7-chloro-2H-isoquinolin-1-one,-   15.    7-Chloro-6-[1-((S)-pyrrolidine-2-carbonyl)-piperidin-4-yloxy]-2H-isoquinolin-1-one,-   16.    7-Chloro-6-[1-(2-dimethylamino-acetyl)-piperidin-4-yloxy]-2H-isoquinolin-1-one,-   17.    6-[1-((S)-2-Amino-propionyl)-piperidin-4-yloxy]-7-chloro-2H-isoquinolin-1-one,-   18.    6-[1-((S)-2-Amino-2-phenyl-acetyl)-piperidin-4-yloxy]-7-chloro-2H-isoquinolin-1-one,-   19.    6-[1-(1-Amino-cyclopropanecarbonyl)-piperidin-4-yloxy]-7-chloro-2H-iso    quinolin-1-one,-   20.    6-[1-((S)-2-Amino-pentanoyl)-piperidin-4-yloxy]-7-chloro-2H-isoquinolin-1-one,-   22.    6-{1-[(S)-2-Amino-3-(4-chloro-phenyl)-propionyl]-piperidin-4-yloxy}-7-chloro-2H-isoquinolin-1-one,-   23.    6-{1-[(S)-2-Amino-3-(4-fluoro-phenyl)-propionyl]-piperidin-4-yloxy}-7-chloro-2H-isoquinolin-1-one,-   24. 6-[1-(2-Amino-acetyl)-piperidin-4-yloxy]-2H-isoquinolin-1-one,-   25.    6-[1-((R)-2-Amino-pentanoyl)-piperidin-4-yloxy]-2H-isoquinolin-1-one,-   26.    6-[1-((S)-2-Amino-4-methyl-pentanoyl)-piperidin-4-yloxy]-2H-isoquinolin-1-one,-   27.    6-{1-[(S)-2-Amino-3-(4-chloro-phenyl)-propionyl]-piperidin-4-yloxy}-2H-isoquinolin-1-one,-   28.    6-[1-(2-Methylamino-acetyl)-piperidin-4-yloxy]-2H-isoquinolin-1-one-   29.    6-[1-((S)-Pyrrolidine-2-carbonyl)-piperidin-4-yloxy]-2H-isoquinolin-1-one,-   30.    6-[1-((S)-2-Amino-3,3-dimethyl-butyryl)-piperidin-4-yloxy]-2H-isoquinolin-1-one,-   31.    6-[1-((S)-2-Amino-butyryl)-piperidin-4-yloxy]-2H-isoquinolin-1-one,-   32.    6-[1-((S)-2-Amino-propionyl)-piperidin-4-yloxy]-2H-isoquinolin-1-one,-   34.    6-[1-((R)-2-Amino-propionyl)-piperidin-4-yloxy]-2H-isoquinolin-1-one,-   35.    6-[1-((S)-2-Amino-2-phenyl-acetyl)-piperidin-4-yloxy]-2H-isoquinolin-1-one,-   36.    6-[1-((S)-2-Amino-hexanoyl)-piperidin-4-yloxy]-2H-isoquinolin-1-one,-   37.    6-[1-((S)-2-Amino-4-methyl-pentanoyl)-piperidin-4-yloxy]-2H-isoquinolin-1-one,-   38.    6-{1-[(S)-2-Amino-3-(4-fluoro-phenyl)-propionyl]-piperidin-4-yloxy}-2H-isoquinolin-1-one,-   39.    6-[1-(2-Amino-2-methyl-propionyl)-piperidin-4-yloxy]-2H-isoquinolin-1-one,    or-   40.    6-[1-(2-Amino-acetyl)-piperidin-4-yloxy]-7-chloro-2H-isoquinolin-1-one,    or their stereoisomeric and/or tautomeric forms and/or their    pharmaceutically acceptable salts.

in another embodiment the present invention relates to a compound offormula (I) selected from

-   41.    [4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-acetic    acid ethyl ester,-   42.    [4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-acetic    acid,-   43.    2-[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-N,N-dimethyl-acetamide,-   44.    2-[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-N-ethyl-acetamide,-   45.    2-[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-N-methyl-acetamide,    or-   46.    2-[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-N-propyl-acetamide,    or their stereoisomeric and/or tautomeric forms and/or their    pharmaceutically acceptable salts.

In a further embodiment, the present invention relates to a compound offormula (I) selected from

-   52. 6-(Azepan-4-yloxy)-2H-isoquinolin-1-one,-   53. 6-((R)-(Pyrrolidin-3-yloxy)-2H-isoquinolin-1-one,-   54. 6-((S)-Pyrrolidin-3-yloxy)-2H-isoquinolin-1-one,-   55. 6-(Azepan-4-yloxy)-7-chloro-2H-isoquinolin-1-one,-   56. 6-((R)-Pyrrolidin-3-yloxy)-7-chloro-2H-isoquinolin-1-one,-   57. 6-((S)-Pyrrolidin-3-yloxy)-7-chloro-2H-isoquinolin-1-one,-   58. 6-(Azetidin-3-yloxy)-7-chloro-2H-isoquinolin-1-one,-   59. 6-(Azepan-4-yloxy)-4,7-dimethyl-2H-isoquinolin-1-one,-   60. 4,7-Dimethyl-6-((R)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-one,-   61. 4,7-Dimethyl-6-((S)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-one,-   62.    4,7-Dimethyl-6-(1-methyl-pyrrolidin-3-yloxy)-2H-isoquinolin-1-one,-   64. 6-(1-Methyl-pyrrolidin-3-yloxy)-2H-isoquinolin-1-one,-   66.    6-((R)-1-Benzyl-pyrrolidin-3-yloxy)-7-chloro-2H-isoquinolin-1-one-   67.    6-((S)-1-Benzyl-pyrrolidin-3-yloxy)-7-chloro-2H-isoquinolin-1-one,-   68. 6-(Azepan-4-yloxy)-7-methyl-2H-isoquinolin-1-one,-   69. 7-Methyl-6-((R)-1-pyrrolidin-3-ylmethoxy)-2H-isoquinolin-1-one,-   70. 7-Methyl-6-((S)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-one, or-   71. 7-Methyl-6-((R)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-one,    more preferably-   55. 6-(Azepan-4-yloxy)-7-chloro-2H-isoquinolin-1-one,-   56. 6-((R)-Pyrrolidin-3-yloxy)-7-chloro-2H-isoquinolin-1-one,-   57. 6-((S)-Pyrrolidin-3-yloxy)-7-chloro-2H-isoquinolin-1-one,-   58. 6-(Azetidin-3-yloxy)-7-chloro-2H-isoquinolin-1-one,-   59. 6-(Azepan-4-yloxy)-4,7-dimethyl-2H-isoquinolin-1-one,-   60. 4,7-Dimethyl-6-((R)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-one,-   61. 4,7-Dimethyl-6-((S)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-one,-   62.    4,7-Dimethyl-6-(1-methyl-pyrrolidin-3-yloxy)-2H-isoquinolin-1-one,-   66.    6-((R)-1-Benzyl-pyrrolidin-3-yloxy)-7-chloro-2H-isoquinolin-1-one-   67.    6-((S)-1-Benzyl-pyrrolidin-3-yloxy)-7-chloro-2H-isoquinolin-1-one,-   68. 6-(Azepan-4-yloxy)-7-methyl-2H-isoquinolin-1-one,-   69. 7-Methyl-6-((R)-1-pyrrolidin-3-ylmethoxy)-2H-isoquinolin-1-one,-   70. 7-Methyl-6-((S)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-one, or-   71. 7-Methyl-6-((R)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-one,    or their stereoisomeric and/or tautomeric forms and/or their    pharmaceutically acceptable salts.

In a further embodiment, the present invention relates to a compound offormula (I) selected from

-   72.    6-[1-((S)-2-Amino-propyl)-piperidin-3-yloxy]-2H-isoquinolin-1-one,-   73.    6-[1-((S)-2-Amino-propyl)-piperidin-4-yloxy]-5-fluoro-4-methyl-2H-isoquinolin-1-one,-   74.    6-[1-((R)-2-Amino-3-hydroxy-propyl)-piperidin-4-yloxy]-2H-isoquinolin-1-one,    or-   75.    6-[1-((R)-2-Amino-3-hydroxy-propyl)-piperidin-4-yloxy]-5-fluoro-4-methyl-2H-isoquinolin-1-one,    or their stereoisomeric and/or tautomeric forms and/or their    pharmaceutically acceptable salts. (Numbering corresponding to    Cpd./Example number)

As in any embodiment of the invention, in the preceding embodimentswhich contain preferred, more preferred, most preferred or exemplarydefinitions of compounds according to the invention, one or more or allof the groups can have any of its preferred, more preferred, mostpreferred definitions specified above or any one or some of the specificdenotations which are comprised by its definitions and are specifiedabove.

Isoquinoline substitution pattern is numbered according to IUPAC rules:

All references to “compound(s) of formula (I)” hereinafter refer tocompound(s) of the formula (I), (II), (III), (III′) and (IV) asdescribed above, and their pharmaceutically acceptable salts, and/or totheir stereoisomeric forms, polymorphs and solvates. Physiologicallyfunctional derivatives as described herein are also included.

Pharmaceutically acceptable salts of compounds of the formula (I) meanboth their organic and inorganic salts as described in Remington'sPharmaceutical Sciences (17th edition, page 1418 (1985)). Because of thephysical and chemical stability and the solubility, preference is givenfor acidic groups inter alia to sodium, potassium, calcium and ammoniumsalts; preference is given for basic groups inter alia to salts ofmaleic acid, fumaric acid, succinic acid, malic acid, tartaric acid,methylsulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acidor of carboxylic acids or sulfonic acids, for example as hydrochlorides,hydrobromides, phosphates, sulfates, methanesulfonates, acetates,lactates, maleates, fumarates, malates, gluconates, and salts of aminoacids, of natural bases or carboxylic acids. The preparation ofpharmaceutically acceptable salts from compounds of the formula (I)which are capable of salt formation, including their stereoisomericforms, takes place in a manner known per se. The compounds of theformula (I) form stable alkali metal, alkaline earth metal or optionallysubstituted ammonium salts with basic reagents such as hydroxides,carbonates, bicarbonates, alcoholates and ammonia or organic bases, forexample trimethyl- or triethylamine, ethanolamine, diethanolamine ortriethanolamine, trometamol or else basic amino acids, for examplelysine, ornithine or arginine. Where the compounds of the formula (I)have basic groups, stable acid addition salts can also be prepared withstrong acids. Suitable pharmaceutically acceptable acid addition saltsof the compounds of the invention are salts of inorganic acids such ashydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric andsulfuric acid, and of organic acids such as, for example, acetic acid,benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic,glycolic, isethionic, lactic, lactobionic, maleic, malic,methanesulfonic, succinic, p-toluenesulfonic and tartaric acid.

Salts with a pharmaceutically unacceptable anion such as, for example,trifluoroacetate likewise belong within the framework of the inventionas useful intermediates for the preparation or purification ofpharmaceutically acceptable salts and/or for use in nontherapeutic, forexample in vitro, applications.

The term “physiologically functional derivative” used herein refers toany physiologically tolerated derivative of a compound of the formula(I) of the invention, for example an N-oxide, which on administration toa mammal such as, for example, a human is able to form (directly orindirectly) a compound of the formula (I) or an active metabolitethereof.

Physiologically functional derivatives include prodrugs of the compoundsof the invention, as described, for example, in H. Okada et al., Chem.Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivoto a compound of the invention. These prodrugs may themselves be activeor not.

The invention relates to compounds of the formula (I), (II), (III) or(III′) in the form of their stereoisomeric forms, which includeracemates, racemic mixtures, pure enantiomers and diastereomers andmixtures thereof.

The compounds of the invention may also exist in various polymorphousforms, for example as amorphous and crystalline polymorphous forms. Allpolymorphous forms of the compounds of the invention belong within theframework of the invention and are a further aspect of the invention.

If radicals or substituents may occur more than once in the compounds ofthe formula (I), they may all, independently of one another, have thestated meaning and be identical or different.

The terms (C₁-C₂)alkyl, (C₁-C₄)alkyl, (C₁-C₆)alkyl, (C₁-C₈)alkyl and thecorresponding alkylene substituents are understood as a hydrocarbonresidue which can be linear, i.e. straight-chain, or branched and has 1,2, 3, 4, 5, 6, 7 or 8 carbon atoms, respectively. This also applies ifan alkyl group occurs as a substituent on another group, for example inan alkoxy group (O-alkyl), S-alkyl or a —O(C₁-C₆)alkylene-O—, analkoxycarbonyl group or an arylalkyl group. Examples of alkyl groups aremethyl, ethyl, propyl, butyl, pentyl or hexyl, the n-isomers of allthese groups, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl,2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl,tert-butyl or tert-pentyl. Alkyl or alkylene groups may—if not otherwisestated—be halogenated once or more, e.g. alkyl groups may befluorinated, e.g. perfluorinated. Examples of halogenated alkyl groupsare CF₃ and CH₂CF₃, OCF₃, SCF₃, or —O—(CF₂)₂—O—.

Alkenyl are, for example, vinyl, 1-propenyl, 2-propenyl (=allyl),2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenylor 1,3-pentadienyl.

Alkynyl are, for example, ethynyl, 1-propynyl, 2-propynyl (=propargyl)or 2-butynyl.

Halogen means fluoro, chloro, bromo or iodo.

(C₃-C₈)cycloalkyl groups are cyclic alkyl groups containing 3, 4, 5, 6,7 or 8 ring carbon atoms like cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cyclooctyl, which can also be substituted and/or contain 1or 2 double bounds (unsaturated cycloalkyl groups) like, for example,cyclopentenyl or cyclohexenyl can be bonded via any carbon atom.

A (C₆-C₁₀)aryl group means an aromatic ring or a ring system whichcomprises two aromatic rings which are fused or otherwise linked, forexample a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- orbeta-tetralon-, indanyl- or indan-1-on-yl group. A preferred(C₆-C₁₀)aryl group is phenyl.

A (C₅-C₁₀)heterocyclyl group means a mono- or bicyclic ring system inwhich one or more carbon atoms can be replaced by one or moreheteroatoms such as, for example 1, 2 or 3 nitrogen atoms, 1 or 2 oxygenatoms, 1 or 2 sulfur atoms or combinations of different hetero atoms.The heterocyclyl residues can be bound at any positions, for example onthe 1-position, 2-position, 3-position, 4-position, 5-position,6-position, 7-position or 8-position. (C₅-C₁₀)heterocyclyl groups may be(1) aromatic [=heteroaryl groups] or (2) saturated or (3) mixedaromatic/saturated.

Suitable (C₅-C₁₀)heterocyclyl group include acridinyl, azocinyl,benzimidazolyl, benzofuryl, benzomorpholinyl, benzothienyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl,4aH-carbazolyl, carbolinyl, furanyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl,chromen-2-onyl, cinnolinyl, decahydroquinolinyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]-tetrahydrofuran, furyl,furazanyl, homomorpholinyl, homopiperazinyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl,3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,prolinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridooxazoles,pyridoimidazoles, pyridothiazoles, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl,thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thienyl, triazolyl, tetrazolyl and xanthenyl.Pyridyl stands both for 2-, 3- and 4-pyridyl. Thienyl stands both for 2-and 3-thienyl. Furyl stands both for 2- and 3-furyl. Also included arethe corresponding N-oxides of these compounds, for example, 1-oxy-2-, 3-or 4-pyridyl.

Substitutions in (C₅-C₁₀)heterocyclyl residues can occur on free carbonatoms or on nitrogen atoms.

Preferred examples of (C₅-C₁₀)heterocyclyl residues are pyrazinyl,pyridyl, pyrimidinyl, pyrazolyl, morpholinyl, pyrrolidinyl, piperazinyl,piperidinyl, thienyl, benzofuryl, quinolinyl, tetrazolyl and triazolyl.

(C₆-C₁₀)aryl and (C₅-C₁₀)heterocyclyl groups are unsubstituted or, ifnot stated otherwise, substituted one or more times, preferably one tothree times, by suitable groups independently selected from halogen, OH,NO₂, N₃, CN, C(O)—(C₁-C₆)alkyl, C(O)—(C₁-C₆)aryl, COOH, COO(C₁-C₆)alkyl,CONH₂, CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, (C₃-C₈)cycloalkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylene-OH, (C₁-C₆)alkylene-NH₂,(C₁-C₆)alkylene-NH(C₁-C₆)alkyl, (C₁-C₆)alkylene-N[(C₁-C₆)alkyl]₂,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, O—(C₁-C₆)alkyl, O—C(O)—(C₁-C₆)alkyl,PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)alkyl, SO₂N[(C₁-C₆)alkyl]₂,S—(C₁-C₆)alkyl; SO—(C₁-C₆)alkyl, SO₂—(C₁-C₆)alkyl,SO₂—N═CH—N[(C₁-C₆)alkyl]₂,

C(NH)(NH₂), NH₂, NH—(C₁-C₆)alkyl, N[(C₁-C₆)alkyl]₂,NH—C(O)—(C₁-C₆)alkyl, NH—C(O)O—(C₁-C₆)alkyl,

NH—SO₂—(C₁-C₆)alkyl, NH—SO₂—(C₆-C₁₀)aryl, NH—SO₂—(C₅-C₁₀)heterocyclyl,N(C₁-C₆)alkyl-C(O)—(C₁-C₆)alkyl, N(C₁-C₆)alkyl-C(O)O—(C₁-C₆)alkyl,

N(C₁-C₆)alkyl-C(O)—NH—(C₁-C₆)alkyl],

(C₆-C₁₀)aryl, (C₁-C₆)alkylene-(C₆-C₁₀)aryl, 0-(C₆-C₁₀)aryl,

O—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, (C₅-C₁₀)heterocyclyl,

(C₁-C₆)alkylene-(C₅-C₁₀)heterocyclyl,O—(C₁-C₆)alkylene-(C₅-C₁₀)heterocyclyl,

wherein the (C₆-C₁₀)aryl or (C₅-C₁₀)heterocyclyl may be substituted oneto 3 times by a group independently selected from halogen, OH, NO₂, CN,O—(C₁-C₆)alkyl, (C₁-C₆)alkyl, NH₂, NH(C₁-C₆)alkyl, N[(C₁-C₆)alkyl]₂,SO₂CH₃, COOH, C(O)O—(C₁-C₆)alkyl, CONH₂, (C₁-C₆)alkylene-O—(C₁-C₆)alkyl,(C₁-C₆)alkylene-O—(C₆-C₁₀)aryl, O—(C₁-C₆)alkylene-(C₆-C₁₀)aryl; orwherein (C₆-C₁₀)aryl is vicinally substituted by a O—(C₁-C₄)alkylene-0group whereby a 5-8-membered ring is formed together with the carbonatoms the oxygen atoms are attached to. Aryl or heterocyclylsubstituents of (C₆-C₁₀)aryl and (C₅-C₁₀)heterocyclyl groups may not befurther substituted by an aryl or heterocyclyl containing group.

Preferred substituents for (C₆-C₁₀)aryl groups are (C₁-C₄)alkyl,O—(C₁-C₄)alkyl, O-phenyl, phenyl, C(O)O—(C₁-C₆)alkyl, C(O)OH,C(O)—(C₁-C₄)alkyl, halogen, NO₂, SO₂NH₂, CN, SO₂—(C₁-C₄)alkyl,SO₂—N═CH—N[(C₁-C₆)alkyl]₂, NH—SO₂—(C₁-C₄)alkyl, NH₂,NH—C(O)—(C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, (C₁-C₄)alkyl-OH,C(O)N[(C₁-C₄)alkyl]₂, CONH(C₁-C₆)alkyl, C(O)NH₂, N[(C₁-C₄)alkyl]₂,(C₁-C₄)alkylene-(C₆-C₁₀)aryl, wherein the (C₆-C₁₀)aryl may be furthersubstituted one to three times, preferably once, by (C₁-C₄)alkyl,(C₁-C₄)alkylene-O—(C₁-C₆)alkyl, (C₆-C₁₀)arylO—(C₁-C₆)alkyl-(C₆-C₁₀)aryl, or may be vicinally substituted by aO—(C₁-C₄)alkylene-0 group whereby a 5-8-membered ring is formed togetherwith the carbon atoms the oxygen atoms are attached to. More preferredsubstituents for (C₆-C₁₀)aryl are halogen, CN, phenyl, O-phenyl,NH—C(O)—(C₁-C₄)alkyl especially NH—C(O)—CH₃, C(O)—(C₁-C₄)alkylespecially C(O)—CH₃, (C₁-C₄)alkyl especially CH₃ or CF₃, O—(C₁-C₄)alkylespecially O—CH₃, SO₂—NH₂, SO₂—(C₁-C₄)alkyl especially SO₂—CH₃ orSO₂—CF₃ or SO₂—N═CH—N[(C₁-C₄)alkyl]₂ especially SO₂—N═CH—N[(CH₃)₂.

In monosubstituted phenyl groups the substituent can be located in the2-position, the 3-position or the 4-position, with the 3-position andthe 4-position being preferred. If a phenyl group carries twosubstituents, they can be located in 2,3-position, 2,4-position,2,5-position, 2,6-position, 3,4-position or 3,5-position. In phenylgroups carrying three substituents the substituents can be located in2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position,2,4,6-position, or 3,4,5-position.

The above statements relating to phenyl groups correspondingly apply todivalent groups derived from phenyl groups, i.e. phenylene which can beunsubstituted or substituted 1,2-phenylene, 1,3-phenylene or1,4-phenylene. The above statements also correspondingly apply to thearyl subgroup in arylalkylene groups. Examples of arylalkylene groupswhich can also be unsubstituted or substituted in the aryl subgroup aswell as in the alkylene subgroup, are benzyl, 1-phenylethylene,2-phenylethylene, 3-phenylpropylene, 4-phenylbutylene,1-methyl-3-phenyl-propylene.

Preferred substituents for (C₅-C₁₀)heterocyclyl groups are (C₁-C₄)alkyl,O—(C₁-C₄)alkyl, (C₁-C₄)alkylene-phenyl, halogen,(C₁-C₄)alkylene-O—(C₁-C₄)alkyl, (C₅-C₁₀)heterocyclyl,(C₁-C₄)alkylene-N[(C₁-C₄)alkyl]₂, or (C₆-C₁₀)aryl, wherein the(C₆-C₁₀)aryl may be further substituted by (C₁-C₄)alkyl, O—(C₁-C₆)alkyl,halogen, (C₁-C₄)alkylene-O—(C₁-C₆)alkyl, O—(C₁-C₆)alkyl-(C₆-C₁₀)aryl, ormay be vicinally substituted by a O—(C₁-C₄)alkylene-0 group whereby a5-8-membered ring is formed together with the carbon atoms the oxygenatoms are attached to. More preferred substituents for(C₅-C₁₀)heterocyclyl groups are (C₁-C₄)alkyl, halogen or phenyl, whereinthe phenyl may be further substituted one to three times, preferablyonce, by halogen, (C₁-C₄)alkyl or O—(C₁-C₄)alkyl.

The general and preferred substituents of (C₆-C₁₀)aryl and(C₅-C₁₀)heterocyclyl groups may be combined with the general andpreferred definitions of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₉, n, m and L asdescribed above.

The present invention therefore also relates to the compounds of theformula (I) and/or their pharmaceutically acceptable salts and/or theirprodrugs for use as pharmaceuticals (or medicaments), to the use of thecompounds of the formula (I) and/or their pharmaceutically acceptablesalts and/or their prodrugs for the production of pharmaceuticals forthe treatment and/or prevention of diseases associated with Rho-kinaseand/or Rho-kinase mediated phosphorylation of myosin light chainphosphatase, i.e. for the treatment and/or prevention of hypertension,pulmonary hypertension, ocular hypertension, retinopathy, and glaucoma,peripheral circulatory disorder, peripheral arterial occlusive disease(PAOD), coronary heart disease, angina pectoris, heart hypertrophy,heart failure, ischemic diseases, ischemic organ failure (end organdamage), fibroid lung, fibroid liver, liver failure, nephropathy,including hypertension-induced, non-hypertension-induced, and diabeticnephropathies, renal failure, fibroid kidney, renal glomerulosclerosis,organ hypertrophy, asthma, chronic obstructive pulmonary disease (COPD),adult respiratory distress syndrome, thrombotic disorders, stroke,cerebral vasospasm, cerebral ischemia, pain, e.g. neuropathic pain,neuronal degeneration, spinal cord injury, Alzheimer's disease,premature birth, erectile dysfunction, endocrine dysfunctions,arteriosclerosis, prostatic hypertrophy, diabetes and complications ofdiabetes, metabolic syndrome, blood vessel restenosis, atherosclerosis,inflammation, autoimmune diseases, AIDS, osteopathy such asosteoporosis, infection of digestive tracts with bacteria, sepsis,cancer development and progression, e.g. cancers of the breast, colon,prostate, ovaries, brain and lung and their metastases.

The present invention furthermore relates to pharmaceutical preparations(or pharmaceutical compositions) which contain an effective amount of atleast one compound of the formula (I) and/or its pharmaceuticallyacceptable salts and a pharmaceutically acceptable carrier, i.e. one ormore pharmaceutically acceptable carrier substances (or vehicles) and/oradditives (or excipients).

The pharmaceuticals can be administered orally, for example in the formof pills, tablets, lacquered tablets, coated tablets, granules, hard andsoft gelatin capsules, solutions, syrups, emulsions, suspensions oraerosol mixtures. Administration, however, can also be carried outrectally, for example in the form of suppositories, or parenterally, forexample intravenously, intramuscularly or subcutaneously, in the form ofinjection solutions or infusion solutions, microcapsules, implants orrods, or percutaneously or topically, for example in the form ofointments, solutions or tinctures, or in other ways, for example in theform of aerosols or nasal sprays.

The pharmaceutical preparations according to the invention are preparedin a manner known per se and familiar to one skilled in the art,pharmaceutically acceptable inert inorganic and/or organic carriersubstances and/or additives being used in addition to the compound(s) ofthe formula (I) and/or its (their) pharmaceutically acceptable saltsand/or its (their) prodrugs. For the production of pills, tablets,coated tablets and hard gelatin capsules it is possible to use, forexample, lactose, corn starch or derivatives thereof, talc, stearic acidor its salts, etc. Carrier substances for soft gelatin capsules andsuppositories are, for example, fats, waxes, semisolid and liquidpolyols, natural or hardened oils, etc. Suitable carrier substances forthe production of solutions, for example injection solutions, or ofemulsions or syrups are, for example, water, saline, alcohols, glycerol,polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Suitablecarrier substances for microcapsules, implants or rods are, for example,copolymers of glycolic acid and lactic acid. The pharmaceuticalpreparations normally contain about 0.5 to about 90% by weight of thecompounds of the formula (I) and/or their pharmaceutically acceptablesalts and/or their prodrugs. The amount of the active ingredient of theformula (I) and/or its pharmaceutically acceptable salts and/or itsprodrugs in the pharmaceutical preparations normally is from about 0.5to about 1000 mg, preferably from about 1 to about 500 mg.

In addition to the active ingredients of the formula (I) and/or theirpharmaceutically acceptable salts and to carrier substances, thepharmaceutical preparations can contain one or more additives such as,for example, fillers, disintegrants, binders, lubricants, wettingagents, stabilizers, emulsifiers, preservatives, sweeteners, colorants,flavorings, aromatizers, thickeners, diluents, buffer substances,solvents, solubilizers, agents for achieving a depot effect, salts foraltering the osmotic pressure, coating agents or antioxidants. They canalso contain two or more compounds of the formula (I) and/or theirpharmaceutically acceptable salts. In case a pharmaceutical preparationcontains two or more compounds of the formula (I) the selection of theindividual compounds can aim at a specific overall pharmacologicalprofile of the pharmaceutical preparation. For example, a highly potentcompound with a shorter duration of action may be combined with along-acting compound of lower potency. The flexibility permitted withrespect to the choice of substituents in the compounds of the formula(I) allows a great deal of control over the biological andphysico-chemical properties of the compounds and thus allows theselection of such desired compounds. Furthermore, in addition to atleast one compound of the formula (I) and/or its pharmaceuticallyacceptable salts, the pharmaceutical preparations can also contain oneor more other therapeutically or prophylactically active ingredients.

When using the compounds of the formula (I) the dose can vary withinwide limits and, as is customary and is known to the physician, is to besuited to the individual conditions in each individual case. It depends,for example, on the specific compound employed, on the nature andseverity of the disease to be treated, on the mode and the schedule ofadministration, or on whether an acute or chronic condition is treatedor whether prophylaxis is carried out. An appropriate dosage can beestablished using clinical approaches well known in the medical art. Ingeneral, the daily dose for achieving the desired results in an adultweighing about 75 kg is from about 0.01 to about 100 mg/kg, preferablyfrom about 0.1 to about 50 mg/kg, in particular from about 0.1 to about10 mg/kg, (in each case in mg per kg of body weight). The daily dose canbe divided, in particular in the case of the administration ofrelatively large amounts, into several, for example 2, 3 or 4, partadministrations. As usual, depending on individual behavior it may benecessary to deviate upwards or downwards from the daily dose indicated.

Furthermore, the compounds of the formula (I) can be used as synthesisintermediates for the preparation of other compounds, in particular ofother pharmaceutical active ingredients, which are obtainable from thecompounds of the formula I, for example by introduction of substituentsor modification of functional groups.

In general, protective groups that may still be present in the productsobtained in the coupling reaction are then removed by standardprocedures. For example, tert-butyl protecting groups, in particular atert-butoxycarbonyl group which is a protection form of an amino group,can be deprotected, i.e. converted into the amino group, by treatmentwith trifluoroacetic acid. As already explained, after the couplingreaction also functional groups can be generated from suitable precursorgroups. In addition, a conversion into a pharmaceutically acceptablesalt or a prodrug of a compound of the formulae (I) can then be carriedout by known processes.

In general, a reaction mixture containing a final compound of theformula (I) or an intermediate is worked up and, if desired, the productis then purified by customary processes known to those skilled in theart. For example, a synthesized compound can be purified using wellknown methods such as crystallization, chromatography or reversephase-high performance liquid chromatography (RP-HPLC) or other methodsof separation based, for example, on the size, charge or hydrophobicityof the compound. Similarly, well known methods such as amino acidsequence analysis, NMR, IR and mass spectrometry (MS) can be used forcharacterizing a compound of the invention.

Isoquinolines and isoquinolinones can by synthesized via a variety ofmethods. The following general schemes illustrate some of the possibleways to access isoquinolones, but do not limit the present invention.

A suitably substituted aldehyde, for example substituted by X or Y beingindependently from each other hydrogen, alkyl, alkoxy or halide attachedin a suitable position, can be reacted with a suitable compound such asfor example an actual of aminoacetaldehyde for example in a solvent likeTHF, chloroform or toluene under acid catalysis by toluene sulfonic acidor another appropriate acid to give imine (ii) wherein Q′ can be forinstance methyl or ethyl, which in turn can be cyclized by differentmethods to the isoquinoline (iii). For example this can be done by Lewisacid catalysis by suitable Lewis acids like titanium tetrachloride,ferrous halides, aluminium halides etc. at temperatures ranging fromambient to 100° C. or by reducing the imine to the corresponding amineby action of a suitable reducing agent like sodium borohydride,converting the amine into an amide or sulphonamide by reaction with asuitable acid chloride and subsequent cyclization to the isoquinoline byaction of an appropriate lewis acid. The isoquinoline (iii) itself canthen be converted to the corresponding N-oxide (iv) by action of asuitable oxidative agent like hydrogen peroxide, m-chloro perbenzoicacid or others at room temperature or elevated temperature. The N-oxide(iv) can then be converted into the 1-chloro-isoquinoline derivative (v)by reacting it with a reagent like phosphorous oxy chloride in orwithout presence of phosphorous pentachloride. The derivative (v) canthen be turned into suitable 1-alkoxy-derivatives by reacting it withvarious alcohols Q-OH like methanol, ethanol or benzyl alcohol in thepresence of a suitable base like sodium hydride and in a suitablesolvent like dimethyl formamide, dimethyl acetamide or others.Alternatively (v) can be directly converted into the isoquinolinonederivative (vii) by reacting it with a reagent like ammonium acetate.

Alternatively isoquinolinones can be obtained by reacting suitable3-formylated or acylated fluorobenzenes (viii), wherein z is for exampleH or alkyl like methyl or ethyl, with a reagent like triethyl phosphonoacetate in the presence of a suitable base like sodium hydride to givethe corresponding cinnamic acid ester, which subsequently is cleaved byaction of a suitable base like potassium hydroxide, sodium hydroxide orlithium hydroxide in a suitable solvent to deliver acid (ix). (ix) canthen be converted in the corresponding acid chloride by well knownmethods, which can be transferred into the acid azide by reaction withsodium azide in a suitable solvent like ether, chloroform or acetone inor without the presence of water. The corresponding azide then can beconverted into isoquinolinone (x) by reacting it in a suitable solventlike diphenylmethane or diphenylether at suitable temperature.

The above obtained 6-Fluoro-isoquinolones, for example (vi), can bereacted with suitable P substituted amino alcohols wherein P is forexample hydrogen, alkyl or a protecting group like for example Boc inthe presence of base such as DBU, cesium carbonate or sodium hydride togive the corresponding alkoxy substituted derivatives (xi). Eventually,this conversion can already be performed at earlier stages of thesynthesis (e.g. by reacting a suitable intermediate). It is understood,that this may require in case of unprotected isoquinolones protection onthe nitrogen or oxygen of the isoquinolone moiety by suitable methods,like reaction with suitably substituted alkyl or benzyl halides in thepresence of base. Isoquinoline derivatives can be obtained by employingfluoro isoquinolines like (iii) in the reaction as described for theconversion of (vi) to (xi), in this particular case OQ equals H. theamino group of such derivatives can be modified accordingly toprocedures described hereafter. The products like (xi) obtained via thismethod can then either be liberated or, if a suitable aminofunctionality is present, be reacted with suitable aldehydes or ketonesin the presence of a reducing agent like sodium triacetoxy borohydride,sodium borohydride or sodium cyanoborohydride in a suitable solvent andin the presence of a water withdrawing agent like molecular sieves or asuitable ortho ester. This amino group may have to be liberated in aninitial step like for example acidic removal of Boc-groups. Furthermorean amino group can be acylated by reacting it with a suitable acidchloride in the precence of a base like triethyl amine or Hünig's baseor by reacting it with a suitable carboxylic acid in the precence of abase like triethylamine of Hünig's base and a coupling reagent like EDC,PyBOP or TOTU.

In case of use of protected isoquinolones, cleavage of the usedprotection groups is required to liberate the desired isoquinolone(xii). This liberation, however, can be performed before or after thereductive amination step, depending on the nature of the usedaldehyde/ketone and the protection group used.

Isoquinolone derivatives like (xii) can be obtained as free bases or asvarious salts like for example hydrochlorides, hydrobromides,phosphates, trifluoroacetates, sulfates or fumarates. The salts obtainedcan be converted into the corresponding free base by either subjectingthem to ion exchange chromatography or for example by alkaline aqueoustreatment and subsequent extraction with suitable organic solvents likefor example methyl tert. butyl ether, chloroform, ethyl acetate orisopropanol/dichloromethane mixtures and subsequent evaporation todryness.

The general methods for the preparation of isoquinoline derivatives asdescribed above can be readily adapted to the preparation of thecompounds of the formula (I). In the following examples the preparationof the compounds of the present invention is outlined in more detail.

Accordingly, the following examples are part of and intended toillustrate but not to limit the present invention.

It is understood that modifications that do not substantially affect theactivity of the various embodiments of this invention are includedwithin the invention disclosed herein.

LC/MS-Methods:

-   Method A:-   Stationary phase: Col YMC Jsphere 33×2-   Gradient: ACN+0.05% TFA:H₂O+0.05% TFA 5:95 (0 min) to 95:5 (3.4 min)    to 95:5 (4.4 min)-   Flow 1 mL/min    Method B:-   Stationary phase: Col YMC Jsphere 33×2-   Gradient: ACN+0.05% TFA:H₂O+0.05% TFA 5:95 (0 min) to 95:5 (2.5 min)    to 95:5 (3.0 min)-   Flow 1 mL/min    Method C:-   Stationary phase: Col YMC Jsphere ODS H80 20×2-   Gradient: ACN:H₂O+0.05% TFA 4:96 (0 min) to 95:5 (2.0 min) to 95:5    (2.4 min)-   Flow 1 mL/min    Method D:-   Stationary phase: Col YMC Jsphere 33×2.1-   Gradient: Grad ACN+0.08% FA:H2O+0.1% FA (Formic Acid) 5:95 (0 min)    to 95:5 (2.5 min) to 95:5 (3 min)-   Flow 1.3 mL/min    Method E:-   Stationary phase: Col YMC Jsphere 33×2-   Gradient: ACN+0.05% TFA:H₂O+0.05% TFA 5:95 (0 min) to 95:5 (2.5 min)    to 95:5 (3.2 min)-   Flow 1.3 mL/min    Method F:-   Stationary phase: Col YMC-Pack Pro C18 RS 33×2.1-   Gradient: Grad ACN+0.1% FA:H₂O+0.1% FA (Formic Acid) 5:95 (0 min) to    95:5 (2.5 min) to 95:5 (3 min)-   Flow 1.3 mL/min

3-Chloro-4-fluoro-benzyl)-(2,2-dimethoxy-ethyl)-amine (1)

100 g (0.63 mol) of 3-chloro-4-fluoro-benzaldehyde were dissolved in 300ml of toluene and 66.3 g (0.63 mol) of aminoacetaldehyd-dimethylacetalwere added at room temperature. After adding 12.0 g (0.06 mol)p-toluenesulfonic acid monohydrate, the reaction was heated in aDean-Stark apparatus for 3 h. The solution was than cooled to roomtemperature and washed twice with saturated NaHCO₃-solution and water.The aqueous solutions are extracted with toluene. The combined organiclayers are dried with MgSO4 and evaporated. The obtainedimine-intermediate is dissolved directly in 300 mL of ethanol and 11.93g (0.32 mol) of sodium borohydride were added in small portions. Afterstirring overnight, 10 mL of acetic acid were added and the solvent wasremoved i. vac. The residue was dissolved in dichloromethane and washedtwice with water. After drying with MgSO₄ and evaporation of thesolvent, 147.0 g of crude product were obtained as a yellow oil, whichwas used without further purification. R_(t)=0.81 min (Method C).Detected mass: 248.2 (M+H⁺).

N-(3-Chloro-4-fluoro-benzyl)-N-(2,2-dimethoxy-ethyl)-4-methyl-benzene-sulfonamide(2)

147.0 g (3-Chloro-4-fluoro-benzyl)-(2,2-dimethoxy-ethyl)-amine (1, crudeproduct) were dissolved in 540 ml of dichloromethane/pyridine (8:1). At0° C. a solution of 145.8 g (1.04 mol) p-toluenesulfonylchloride in 200ml of dichloromethane was added. After 5 h at room temperatureadditional 20 ml of pyridine, 29.16 g (0.15 mol)p-toluene-sulfonylchloride and a catalytic amount of DMAP were added.The solution was stirred at room temperature for 7 h and then refluxedfor additional 4 h. Again 29.16 g (0.15 mol) p-toluene-sulfonylchlorideand a catalytic amount of DMAP were added and the mixture was stirredovernight. For workup, the solution was washed twice with 2 N HCl andtwice with saturated NaHCO₃-solution. The organic layer was dried withMgSO₄ and evaporated. Final silicagel chromatography (heptane/ethylacetate 4:1) gave 155 g of the title compound as a yellow oil.R_(t)=1.80 min (Method B). Detected mass: 370.2 (M-OMe⁻).

7-Chloro-6-fluoro-isoquinoline (3)

343.6 (2.54 mol) of AlCl₃ were suspended in 1.1 l of dichloromethane andwere stirred for 30 min with a mechanical stirrer. To this suspension, asolution of 204 g (0.51 mol)(N-(3-Chloro-4-fluoro-benzyl)-N-(2,2-dimethoxy-ethyl)-4-methyl-benzene-sulfonamide(2) was added and the mixture was stirred at room temperature for 5 h.After standing overnight, the reaction suspension was poured on ice, theorganic layer was separated and the aqueous phase was extracted twicewith dichloromethane. The combined organic layers were washed twice with1 N NaOH and saturated NaHCO3-solution, dried with MgSO4 and evaporated.The obtained crude product was purified by silicagel chromatography(heptane/ethyl acetate 1:1), which gave 61.3 g of the title compound.R_(t)=0.73 min (Method B). Detected mass: 182.1 (M+H⁺).

7-Chloro-6-fluoro-isoquinoline 2-oxide (4)

25 g (137.7 mmol) of 7-Chloro-6-fluoro-isoquinoline (3) were indissolved in 500 ml of dichloromethane. At room temperature 50.9 g(206.5 mmol) of 3-Chloro-benzene-carboperoxoic acid (70%) were added andthe mixture was stirred at room temperature until complete conversion isachieved. For workup, the precipitate was filtered off and washed withdichloromethane. The filtrate was washed twice with NaHCO₃-solution. Thelayers were separated and the aqueous phase was extracted twice withdichloromethane. The organic phases were dried with MgSO₄ andevaporated. The so obtained solid material (18.4 g) was used withoutfurther purification. R_(t)=0.87 min (Method C). Detected mass:198.1/200.1 (M+H⁺).

1,7-Di-chloro-6-fluoro-isoquinoline (5)

2.6 g (12.0 mmol) of 7-Chloro-6-fluoro-isoquinoline 2-oxide (4) wereheated in 40 ml of POCl₃ at reflux for 4 h. After the mixture has cooleddown to room temperature, it was poured on ice. The aqueous solution wasextracted three times with dichloromethane. The combined organic layerswere dried with MgSO₄ and evaporated to yield 2.91 g of the titlecompound, which was used without further purification. R_(t)=2.34 min(Method A). Detected mass: 216.0/218.0 (M+H⁺).

4-(1-Benzyloxy-7-chloro-isoquinolin-6-yloxy)-piperidine-1-carboxylicacid tert-butyl-ester (6)

289.8 mg (1.44 mmol) of 4-hydroxy-piperidine-1-carboxylic acidtert-butyl-ester were dissolved in 10 ml of dimethyl acetamide and 57.6mg (1.44 mmol) of sodium hydride (60%) were added. The reaction mixturewas stirred at room temperature. After 30 minutes a solution of 310 mg(1.44 mmol) of 1,7-dichloro-6-fluoro-isoquinoline (5) in 3 ml ofdimethyl acetamide was added and the mixture was stirred at roomtemperature for 1 h to complete conversion. Then 155.7 mg (1.44 mmol) ofbenzyl alcohol followed by 57.6 mg (1.44 mmol) of sodium hydride (60%)were added and stirring was continued at room temperature. To reachcomplete conversion, 0.5 equivalents of benzyl alcohol and sodiumhydride were added twice, after 2 h and standing overnight. For workingup, the solvent was evaporated, the residue was taken up indichloromethane, washed twice with H₂O, dried with MgSO₄ and evaporated.Final purification was accomplished by preparative HPLC.

7-Chloro-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one-hydrochloride (7)

254 mg (0.52 mmol) of4-(1-Benzyloxy-7-chloro-isoquinolin-6-yloxy)-piperidine-1-carboxylicacid tert-butyl-ester (6) were stirred in methanol/2 N HCl (1:1) at roomtemperature overnight. The solvent was removed i. vac. and the residuewas purified by preparative HPLC. The product fractions were evaporatedand dissolved in 2 N HCl. Lyophilization results in 57 mg of the desiredcompound. R_(t)=0.95 min (Method B). Detected mass: 279.1 (M+H⁺).

General procedure for the acylation reaction of7-Chloro-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one (7)

0.74 mmol of the carboxylic acid derivative were dissolved in 10 ml ofDMF. After adding 0.74 mmol of triethylamine, 0.74 mmol of TOTU wereadded at 0° C. and the solution was stirred at room temperature for 30minutes. This solution was than added to a solution of 0.74 mmol7-chloro-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one (7, free base) in 10ml DMF at 0° C. Stirring is continued at room temperature until completeconversion is achieved. For isolation, the solvent was removed i. vac.and the residue was dissolved in dichloromethane. The solution waswashed with water and dried over MgSO₄. The obtained crude products werepurified by prep. HPLC. The product fractions were evaporated and theresidues dissolved in 2 N HCl. In the case of Boc-protected product, the2 NHCl-solutions were stirred at room temperature until completecleavage of the Boc-group is achieved. After evaporation of the aqueoussolution, the compounds were dissolved in water and freeze dried to givethe desired compounds as HCl-salts.

The compounds described in the following table 1 were obtained usingthis general procedure.

TABLE 1 Comp. R_(t) Mass Me- No. Carboxylic acid derivative Product[min] [M + H⁺] thod Chemical Name 8

0.87 350.1 B 7-Chloro-6-[1-(2- methylamino-acetyl)-piperidin-4-yloxy]-2H- isoquinolin-1-one 9

1.47 466.2 B 2-{2-[4-(7-Chloro-1-oxo- 1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-2- oxo-ethyl}-isoindole-1,3- dione 10

1.08 392.3 B 6-[1-(2-Amino-3,3- dimethyl-butyryl)-piperidin-4-yloxy]-7-chloro-2H- isoquinolin-1-one 11

0.90 350.1 B 6-[1-(2-Amino-propionyl)- piperidin-4-yloxy]-7-chloro-2H-isoquinolin-1-one 12

0.92 364.2 B 6-[1-(2-Amino-2-methyl- propionyl)-piperidin-4-yloxy]-7-chloro-2H- isoquinolin-1-one 13

0.95 364.2 B 6-[1-((S)-2-Amino-butyryl)- piperidin-4-yloxy]-7-chloro-2H-isoquinolin-1-one 14

1.10 392.2 B 6-[1-((S)-2-Amino-4- methyl-pentanoyl)-piperidin-4-yloxy]-7-chloro- 2H-isoquinolin-1-one 15

1.00 376.2 B 7-Chloro-6-[1-((S)- pyrrolidine-2-carbonyl)-piperidin-4-yloxy]-2H- isoquinolin-1-one 16

0.91 364.2 B 7-Chloro-6-[1-(2- dimethylamino-acetyl)-piperidin-4-yloxy]-2H- isoquinolin-1-one 17

0.98 350.1 B 6-[1-((S)-2-Amino- propionyl)-piperidin-4-yloxy]-7-chloro-2H- isoquinolin-1-one 18

1.15 412.1 B 6-[1-((S)-2-Amino-2- phenyl-acetyl)-piperidin-4-yloxy]-7-chloro-2H- isoquinolin-1-one 19

0.96 362.1 B 6-[1-(1-Amino- cyclopropanecarbonyl)-piperidin-4-yloxy]-7-chloro- 2H-isoquinolin-1-one 20

1.09 378.2 B 6-[1-((S)-2-Amino- pentanoyl)-piperidin-4-yloxy]-7-chloro-2H- isoquinolin-1-one 22

1.25 460.1 B 6-{1-[(S)-2-Amino-3-(4- chloro-phenyl)-propionyl]-piperidin-4-yloxy}-7- chloro-2H-isoquinolin-1- one 23

1.20 444.1 B 6-{1-[(S)-2-Amino-3-(4- fluoro-phenyl)-propionyl]-piperidin-4-yloxy}-7- chloro-2H-isoquinolin-1- one

The following products were obtained, using 51 as isoquinolinonebuilding block:

The compounds were obtained as HCl salts. In case of 24, cleavage of thephthalimide group was achieved in analogous manner as described for 40(Table 2).

TABLE 2 Com- Mass pound Carboxylic acid R_(t) [M + Me- No. derivativeProduct [min] H⁺] thod Chemical name 24

0.35 302.3 B 6-[1-(2-Amino-acetyl)- piperidin-4-yloxy]-2H-isoquinolin-1-one 25

1.00 344.2 B 6-[1-((R)-2-Amino- pentanoyl)-piperidin-4- yloxy]-2H-isoquinolin-1-one 26

1.07 352.2 B 6-[1-((S)-2-Amino-4- methyl-pentanoyl)-piperidin-4-yloxy]-2H- isoquinolin-1-one 27

1.19 426.2 B 6-{1-[(S)-2- Amino-3-(4- chloro-phenyl)- propionyl]-piperidin-4- yloxy}-2H- isoquinolin-1-one 28

0.80 316.2 B 6-[1-(2-Methylamino- acetyl)-piperidin-4- yloxy]-2H-isoquinolin-1-one 29

0.88 342.2 B 6-[1-((S)-Pyrrolidine-2- carbonyl)-piperidin-4- yloxy]-2H-isoquinolin-1-one 30

1.06 358.2 B 6-[1-((S)-2-Amino-3,3- dimethyl-butyryl)- piperidin-4-yloxy]-2H- isoquinolin-1- one 31

0.90 330.2 B 6-[1-((S)-2-Amino- butyryl)- piperidin-4-yloxy]-2H-isoquinolin-1-one 32

0.92 316.2 B 6-[1-((S)-2-Amino- propionyl)-piperidin-4- yloxy]-2H-isoquinolin-1-one 33

1.38 432.2 B 2-{2-Oxo-2- [4-(1-oxo-1,2- dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]- ethyl}-isoindole- 1,3-dione 34

0.82 316.2 B 6-[1-((R)-2-Amino- propionyl)-piperidin-4- yloxy]-2H-isoquinolin-1-one 35

1.02 378.2 B 6-[1-((S)-2-Amino-2- phenyl-acetyl)- piperidin-4-yloxy]-2H- isoquinolin-1-one 36

1.07 358.2 B 6-[1-((S)-2-Amino- hexanoyl)-piperidin-4- yloxy]-2H-isoquinolin-1-one 37

1.07 358.2 B 6-[1-((S)-2-Amino-4- methyl-pentanoyl)-piperidin-4-yloxy]-2H- isoquinolin-1-one 38

1.11 410.2 B 6-{1-[(S)-2-Amino-3-(4- fluoro-phenyl)- propionyl]-piperidin-4-yloxy}-2H- isoquinolin-1-one 39

0.95 330.2 B 6-[1-(2-Amino- 2-methyl- propionyl)-piperidin-4- yloxy]-2H-isoquinolin-1-one

6-[1-(2-Amino-acetyl)-piperidin-4-yloxy]-7-chloro-2H-isoquinolin-1-one(40)

140 mg (0.35 mmol) of2-{2-[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-isoindole-1,3-dione(9) were dissolved in 5 mL of ethanol and 30.1 mg (0.60 mmol) ofhydrazine hydrate were added at room temperature. After 2 h at roomtemperature another 30.1 mg (0.60 mmol) of hydrazine hydrate were addedand the reaction mixture was heated to 80° C. After 16 h, the solventwas evaporated i. vac. and the crude product was purified by preparativeHPLC. Evaporation of the product fractions gave the desired compound astrifluoroacetate, which was dissolved in 2 N HCl. The solvent wasevaporated i. vac., the residue was dissolved in H₂O. Afterlyophilisation, the title compound was isolated as HCl-salt. R_(t)=0.91min (Method B). Detected mass: 336.1 (M+H⁺).

[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-aceticacid ethyl ester (41)

1.5 g (5.38 mmol) of 7-Chloro-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one(7, free base) were dissolved in 100 mL of methanol. At roomtemperature, 1.09 g (10.8 mmol) of triethylamine, 3.23 g (53.8 mmol) ofacetic acid, 7.63 g (33.6 mmol) of glyoxylic acid ethyl ester andmolecular sieves (4 A) were added, followed by 253.6 mg (4.04 mmol) ofsodium cyanoborohydride. After stirring for 2 h at room temperature, thereaction mixture was filtered and the filtrate was evaporated i. vac.The residue was dissolved in dichloromethane and washed with 1 N NaOHand sat. NaCl-solution. The organic layer was dried with MgSO₄ andevaporated. The obtained crude product was used without furtherpurification.

[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-aceticacid (42)

1.56 g (4.27 mmol)[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-aceticacid ethyl ester (41) were dissolved in 20 mL of methanol and 20 ml of2N NaOH were added. After stirring for 1 h at room temperature, thesolvent was removed i. vac. and the residue was dissolved in water. Theaqueous solution was neutralized by adding 2 N HCl. Filtration of theprecipitate and drying gave 856 mg of the title compound. R_(t)=0.82 min(Method B). Detected mass: 337.1 (M+H⁺).

2-[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-N,N-dimethyl-acetamide(43)

The title compound was synthesized following the method described for2-[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-acetamide(42), using a 40% aqueous solution of dimethylamine. After finalpurification by preparative HPLC, the trifluoroacetate was obtained,which was dissolved in 2 N HCl. Evaporation of the solvent andlyophilisation of an aqueous solution of the residue gave the titlecompound as HCl-salt. R_(t)=0.80 min (Method B). Detected mass: 364.1(M+H⁺).

2-[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-N-ethyl-acetamide(44)

The title compound was synthesized following the method described for2-[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-acetamide(43), using a 70% aqueous solution of ethylamine. After finalpurification by preparative HPLC, the trifluoroacetate was obtained,which was dissolved in 2 N HCl. Evaporation of the solvent andlyophilisation of an aqueous solution of the residue gave the titlecompound as HCl-salt. R_(t)=0.80 min (Method C). Detected mass: 364.2(M+H⁺).

2-[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-N-methyl-acetamide(45)

The title compound was synthesized following the method described for2-[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-acetamide(43), using a 40% aqueous solution of Methylamine. After finalpurification by preparative HPLC, the trifluoroacetate was obtained,which was dissolved in 2 N HCl. Evaporation of the solvent andlyophilisation of an aqueous solution of the residue gave the titlecompound as HCl-salt. R_(t)=0.77 min (Method C). Detected mass: 350.2(M+H⁺).

2-[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-N-propyl-acetamide(46)

The title compound was synthesized following the method described for2-[4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-piperidin-1-yl]-acetamide(43), using propylamine. R_(t)=0.98 min (Method B). Detected mass: 378.2(M+H⁺).

6-Fluoro-isoquinolinone (47)

4.8 mL (90.3 mmol, 1.5 eq.) of thionyl chloride was added portionwise toa solution of 10 g (60.2 mmol) of 3-fluoro cinnamic acid in 44 mL ofchloroform and 1 mL of DMF. The reaction was heated to reflux for 2.5 h.Then the solvents were distilled to to yield 11.4 g of the crude acidchloride, which was used without any further purification.

The acid chloride was dissolved in 45 mL of acetone. At 0° C. 8.03 g ofNaN₃ (123.5 mmol, 2 eq.) were added portionwise. Then 41 mL of waterwere added while the temperature was kept below 5° C. The reaction wasstirred for another 1.5 h. Then 55 mL of chloroform were added. Themixture was extracted with 80 mL of water followed by 40 mL of brine.After drying over Na₂SO₄ and filtration 14 mL of diphenyl ether wereadded and most of the chloroform was removed in vacuo (without heating).A total removal of the chloroform should be avoided.

The solution containing the azide, diphenyl ether and the remainingchloroform was added dropwise at 260° C. within 15 minutes to a solutionof 10 mL of tributyl amine in 97 mL of diphenyl ether. A vigorousreaction can be observed during the addition. The reaction was stirredfor another 20 minutes at 260° C. After cooling to room temperature 270mL of n-heptane were added. The precipitated product was filtered offand washed with ether to yield 5.65 g of the title compound. MS (DCI)Detected mass: 164.0 (M+H⁺).

6-Fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (48)

169 μL of p-methoxybenzylchloride (1.24 mmol, 1.1 eq) were added to asuspension of 200 mg of 6-fluoro-isoquinolinone (13) (1.13 mmol) and 368mg of Cs₂CO₃ (1.36 mmol, 1.2 eq) in 3 mL of DMF. The mixture was stirredfor 2 h and then poured on ice. The precipitate was filtered, washedwith water and dried to yield 300 mg of the title compound. LCMS MethodB, retention time 1.76 min, detected mass 284.14 [M+H]⁺

4,7-Dimethyl-6-Fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (49)

4,7-Dimethyl-6-Fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (49) wasobtained in a similar fashion as described for (48), starting from3-(3-Fluoro-4-methyl phenyl)-but-2-enoic acid. R_(t)=1.96 min (MethodB). Detected mass: 312.1 (M+H⁺).

5,6-Difluoro-2-(4-methoxy-benzyl)-4-methyl-2H-isoquinolin-1-one (50)

5,6-Difluoro-2-(4-methoxy-benzyl)-4-methyl-2H-isoquinolin-1-one (50) wasobtained in a similar fashion as described for (48), starting from3-(2,3-Difluorophenyl)-but-2-enoic acid. R_(t)=1.94 min (Method B).Detected mass: 316.1 (M+H⁺).

6-(Piperidin-4-yloxy)-2H-isoquinolin-1-one (51)

117 mg (0.58 mmol) of 4-hydroxy-piperidine-1-carboxylicacid-tert-butylester were dissolved in 2 mL of N,N-dimethyl acetamide.Under an argon atmosphere, 63.6 mg (2.7 mmol) of sodium hydride wereadded and the mixture was stirred at room temperature. After 30 minutes,150 mg (0.53 mmol) of 6-fluoro-2-(4-methoxybenzyl)-2H-isoquinolin-1-one(48) were added and the solution was heated to 80° C. for 1 h. Themixture was poured in water and extracted with chloroform. The combinedorganic layers were dried over Na₂SO₄, filtered and evaporated. Thecrude intermediate was purified by preparative HPLC. The protectinggroups were removed by dissolving the protected intermediate in 2 mL ofTFA and heating the reaction to 150° C. for 2 h in a microwave reactor.The reaction mixture was quenched with methanol and evaporated todryness. The remaining residue was taken up in dichloromethane,extracted three times with 1N HCl and the combined aqueous layer wasextracted once with dichloromethane. The combined aqueous layer waslyophilized, the remainder was taken up in water twice and lyophilizedagain to give the product as HCl salt. The purity of the obtainedproduct is sufficient, but eventually occurring impurities could beremoved by silica gel chromatography or HPLC. R_(t)=0.75 min (Method B).Detected mass: 245.1 (M+H⁺).

The following compounds were prepared in a similar fashion, using thedesignated starting materials, they were obtained as their HCl salts.

TABLE 3 Com- pound iso- R_(t) Mass No. quinolinone Alcohol Product [min][M + H⁺] Mtd. Chemical name 52 51

0.82 259.1 B 6-(Azepan-4-yloxy)-2H- isoquinolin-1-one 53 51

0.54 231.2 B 6-((R)-(Pyrrolidin-3- yloxy)-2H-isoquinolin-1- one 54 51

0.58 231.2 B 6-((S)-Pyrrolidin-3- yloxy)-2H-isoquinolin-1- one 55 7

1.00 293.1 B 6-(Azepan-4-yloxy)-7- chloro-2H-isoquinolin-1- one 56 7

0.71 265.1 B 6-((R)-Pyrrolidin-3- yloxy)-7-chloro-2H- isoquinolin-1-one57 7

0.76 265.1 B 6-((S)-Pyrrolidin-3- yloxy)-7-chloro-2H- isoquinolin-1-one58 7

0.67 251.1 B 6-(Azetidin-3-yloxy)-7- chloro-2H-isoquinolin-1- one 59 49

0.83 287.2 A 6-(Azepan-4-yloxy)-4,7- dimethyl-2H- isoquinolin-1-one 6049

0.72 259.2 A 4,7-Dimethyl-6-((R)- pyrrolidin-3-yloxy)-2H-isoquinolin-1-one 61 49

0.74 259.2 A 4,7-Dimethyl-6-((S)- pyrrolidin-3-yloxy)-2H-isoquinolin-1-one 62 49

0.74 273.2 A 4,7-Dimethyl-6-(1- methyl-pyrrolidin-3-yloxy)-2H-isoquinolin-1- one 63 51

0.75 245.2 B 6-(Piperidin-3-yloxy)-2H- isoquinolin-1-one 64 51

0.62 245.1 B 6-(1-Methyl-pyrrolidin-3- yloxy)-2H-isoquinolin-1- one 6550

1.00 277.5 D 5-Fluoro-4-methyl-6- (piperidin-4-yloxy)-2H-isoquinolin-1-one

6-((R)-1-Benzyl-pyrrolidin-3-yloxy)-7-chloro-2H-isoquinolin-1-one (66)

104 mg of 60 were suspended in 2 mL of dry dichloromethane. 71 μL oftriethylamine, 105 μL of benzaldehyde, 26 μL of acetic acid and 150 mgof powdered molecular sieves were added. The solution was stirred for 2h and 220 mg of sodium triacetoxy borohydride were added. The solutionwas stirred for 3 h. The reaction mixture is poured in 1 N NaOH, theaqueous layer was extracted with dichloromethane:isopropanol 3:1 and theorganic layer was dried over sodium sulphate and evaporated to dryness.The obtained material was purified by silica gel chromatography.R_(t)=1.14 min (Method B). Detected mass: 355.1 (M+H⁺).

6-((S)-1-Benzyl-pyrrolidin-3-yloxy)-7-chloro-2H-isoquinolin-1-one (67)

6-((S)-1-Benzyl-pyrrolidin-3-yloxy)-7-chloro-2H-isoquinolin-1-one (67)was obtained in an analogous fashion as described for (66). R_(t)=1.11min (Method B). Detected mass: 355.1 (M+H⁺).

6-(Azepan-4-yloxy)-7-methyl-2H-isoquinolin-1-one (68)

a) 6-Fluoro-7-methyl-2H-isoquinolin-1-one

To a solution of 10.0 g (55.5 mmol) of 3-fluoro-4-methyl-cinnamic acidin 80 ml acetone were subsequently added at 0° C. 6.74 g (66.6 mmol)triethylamine in 10 ml acetone followed by 7.83 g (72.2 mmol) ethylchloroformate. After stirring for 2 h at 0 to 5° C. a solution of 4.0 g(61.1 mmol) sodium azide in 9.5 ml water was added. After stirring for 1additional h the reaction mixture was poured onto 200 ml ice water andextracted twice with chloroform. The organic phase was dried overmagnesium sulfate, 40 ml diphenylether were added and the chloroform wascautiously removed in vacuo. The residue was then added dropwise into 50ml of diphenylether which had been preheated to 245° C. After completeaddition it was stirred for 1 further h at 230-250° C. After coolingdown to 150° C. the reaction mixture was poured into 270 ml heptane andafter further cooling in an ice bath the precipitated product wasfiltered by suction and 4.1 g 6-fluoro-7-methyl-2H-isoquinolin-1-onewere obtained.

b) 6-Fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one

To a solution of 9.17 g (51.8 mmol) of6-fluoro-7-methyl-2H-isoquinolin-1-one in 80 ml DMF were added 20.2 g(62.1 mmol) caesium carbonate and then 8.92 g (56.9 mmol)4-methoxybenzylchloride. After stirring at room temperature for 90minutes the reaction mixture was poured into 600 ml water, stirred for 1h, and then the precipitated product was filtrated by suction. From themother liquor additional producted was isolated by chromatography withheptane/ethyl acetate (80:20). The combined products were recrystallizedfrom ethyl acetate and 8.39 g6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one werereceived.

c) 6-(Azepan-4-yloxy)-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one

A solution of 58 mg (0.51 mmol) azepan-4-ol in 5 ml dimethylacetamidewas stirred with 45 mg (1.52 mmol) 80 percent sodium hydride for 45minutes at room temperature. Then 150 mg (0.51 mmol)6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one indimethylacetamide was added. The reaction mixture was heated to 80° C.for 3 days during which additional amounts of azepan-4-ol and sodiumhydride were added until complete conversion of the6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one wasobtained. The reaction mixture was slowly added to 10 ml water and after1 h of stirring the product was isolated by filtration and driedovernight in vacuum. 82 mg of6-(azepan-4-yloxy)-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-onewere obtained.

d) 6-(Azepan-4-yloxy)-7-methyl-2H-isoquinolin-1-one hydrochloride

81 mg of6-(azepan-4-yloxy)-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-onewere dissolved in 0.47 trifluoroacetic acid and heated for 2 h in amicrowave oven at 150° C. Then the excess trifluoroacetic acid wasdistilled off in vacuo and the residue was diluted with 10 ml 1 Mhydrochloric acid. The aqueous phase was washed with methylene chloridetwice and then freeze dried. After stirring of the residue inisopropanol and filtration 15 mg of6-(azepan-4-yloxy)-7-methyl-2H-isoquinolin-1-one as the hydrochloridewere obtained. R_(t)=0.77 min (Method C). Detected mass: 273.2 (M+H⁺).

7-Methyl-6-((R)-1-pyrrolidin-3-ylmethoxy)-2H-isoquinolin-1-one (69)

a)(R)-3-[2-(4-Methoxy-benzyl)-7-methyl-1-oxo-1,2-dihydro-isoquinolin-6-yloxymethyl]pyrrolidine-1-carboxylicacid tert-butyl ester

A solution of 271 mg (1.35 mmol)(R)-3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester in 12ml dimethylacetamide was stirred with 121 mg (4.0 mmol) 80 percentsodium hydride for 30 minutes at room temperature. Then a solution of0.5 g (1.68 mmol)6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one (68, step b)in 20 ml dimethylacetamide was added. The reaction mixture was stirredat room temperature overnight, after which time the same amounts of(R)-3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester andsodium hydride were added to drive the reaction to completion. Afterfurther 3 h stirring, the reaction mixture was slowly added to 15 mlwater and after 1 h the product was isolated by filtration and driedovernight in vacuum. 0.53 g of(R)-3-[2-(4-Methoxy-benzyl)-7-methyl-1-oxo-1,2-dihydro-isoquinolin-6-yloxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester were obtained.

b) 7-Methyl-6-((R)-1-pyrrolidin-3-ylmethoxy)-2H-isoquinolin-1-onehydrochloride

0.53 g (1.1 mmol)(R)-3-[2-(4-Methoxy-benzyl)-7-methyl-1-oxo-1,2-dihydro-isoquinolin-6-yloxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester were dissolved in 2.5 g (22 mmol) trifluoroaceticacid. After 1 h at room temperature the mixture was heated for 2 h in amicrowave oven at 150° C. Then the excess trifluoroacetic acid wasdistilled off in vacuo and the residue was diluted with 10 ml 1 Mhydrochloric acid. The aqueous phase was washed with methylene chloridetwice and then it was freeze dried to give 0.11 g7-Methyl-6-((R)-1-pyrrolidin-3-ylmethoxy)-2H-isoquinolin-1-one as thehydrochloride. R_(t)=0.82 min (Method B). Detected mass: 259.1 (M+H⁺).

7-Methyl-6-((S)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-one (70)

a)(S)-3-[2-(4-Methoxy-benzyl)-7-methyl-1-oxo-1,2-dihydro-isoquinolin-6-yloxy]-pyrrolidine-1-carboxylicacid tert-butyl ester

A solution of 252 mg (1.35 mmol) (S)-3-hydroxy-pyrrolidine-1-carboxylicacid tert-butyl ester in 12 ml dimethylacetamide was stirred with 81 mg(2.7 mmol) 80 percent sodium hydride for 30 minutes at room temperature.Then a solution of 0.4 g (1.3 mmol)6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one (68, step b)in 15 ml dimethylacetamide was added. The reaction mixture was heated to80° C. for 2 h during which time a clear solution was obtained. Thereaction mixture was slowly added to 10 ml water and after 30 minutes ofstirring the product was isolated by filtration and dried overnight invacuum. 0.54 g of(S)-3-[2-(4-Methoxy-benzyl)-7-methyl-1-oxo-1,2-dihydro-isoquinolin-6-yloxy]-pyrrolidine-1-carboxylicacid tert-butyl ester were obtained.

b) 7-Methyl-6-((S)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-onehydrochloride

0.54 g (1.2 mmol)(S)-3-[2-(4-Methoxy-benzyl)-7-methyl-1-oxo-1,2-dihydro-isoquinolin-6-yloxy]-pyrrolidine-1-carboxylicacid tert-butyl ester were dissolved in 2.7 g (23 mmol) trifluoroaceticacid. After 1 h at room temperature the mixture was heated for 2 h in amicrowave oven at 150° C. Then the excess trifluoroacetic acid wasdistilled off in vacuo and the residue was diluted with 10 ml 1 Mhydrochloric acid. The aqueous phase was washed with methylene chloridetwice and then it was freeze dried to give 0.256 g7-Methyl-6-((S)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-one as thehydrochloride. R_(t)=0.90 min (Method B). Detected mass: 245.2 (M+H⁺).

7-Methyl-6-((R)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-one (71)

a)2-(4-Methoxy-benzyl)-7-methyl-6-((R)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-onehydrochloride

A solution of 125 mg (1.0 mmol) (R)-3-pyrrolidinol hydrochloride in 9 mldimethylacetamide was stirred with 61 mg (2.0 mmol) 80 percent sodiumhydride for 30 minutes at room temperature. Then a solution of 0.3 g(1.0 mmol) 6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one(68, step b) in 10 ml dimethylacetamide was added. The reaction mixturewas stirred at 80° C. for 12 h, after which time the same amounts of(R)-3-pyrrolidinol hydrochloride and sodium hydride were added to drivethe reaction to completion. After further 2 days heating to 80° C., thereaction mixture was slowly added to 8 ml water and extracted withmethylenechloride. After evaporation the residue was dissolved in 20 mlof 1 M hydrochloric acid and washed with ethyl acetate. The aqueousphase was lyophylisized to give 247 mg of2-(4-Methoxy-benzyl)-7-methyl-6-((R)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-onehydrochloride.

b) 7-Methyl-6-((R)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-onehydrochloride

245 mg of2-(4-Methoxy-benzyl)-7-methyl-6-((R)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-onehydrochloride were dissolved in 1.4 g trifluoroacetic acid and themixture was heated for 2 h in a microwave oven at 150° C. Then theexcess trifluoroacetic acid was distilled off in vacuo and the residuewas diluted with 10 ml 1 M hydrochloric acid. The aqueous phase waswashed with methylene chloride twice and then it was freeze dried togive 134 mg7-Methyl-6-((R)-1-pyrrolidin-3-ylmethoxy)-2H-isoquinolin-1-onehydrochloride. R_(t)=0.92 min (Method B). Detected mass: 245.1 (M+H⁺).

General Procedure for the Reductive Amination Reaction:

0.243 mmol of 6-(piperidin-4-yloxy)-2H-isoquinolin-1-one-hydrochloride(51) or of another suitable amine, 0.243 mmol of the aldehyde and 0.365mmol triethylamine were stirred in 3 mL HC(OMe)₃ for 1 h at roomtemperature. The mixture was cooled to −10° C., 1.75 mL of a freshlyprepared DMF solution containing 1.215 mmol NaHB(OAc)₃ and 1.215 mmol ofHOAc were added. Stirring was continued at −10° C. for 30 min, themixture is then allowed to warm to room temperature and left at roomtemperature overnight. 0.5 mL of water was added and the mixture wasevaporated, dissolved in DMF and purified by preparative HPLC. Thepurified products were dissolved in 1 mL of HCl in isopropanol (5-6M)and stirred, until removal of Boc or isopropylidene groups is complete.2 mL of water were added and the solution was freeze-dried to yield thehydrochlorides of the products.

The following compounds shown in the subsequent Table were synthesizedin a similar fashion as described in this general procedure and obtainedas hydrochloride salts (Table 4):

TABLE 4 Com- pound Isoquin- No. Aldehyde olinone Product [M + H]⁺ R_(t)[min] Method Chemical Name 72

63

302.2 0.64 B 6-[1-((S)-2-Amino- propyl)-piperidin-3-yloxy]-2H-isoquinolin- 1-one 73

65

334.2 0.80 B 6-[1-((S)-2-Amino- propyl)-piperidin-4- yloxy]-5-fluoro-4-methyl-2H- isoquinolin-1-one 74

51

318.3 0.50 A 6-[1-((R)-2-Amino-3- hydroxy-propyl)-piperidin-4-yloxy]-2H- isoquinolin-1-one 75

51

350.2 0.82 B 6-[1-((R)-2-Amino-3- hydroxy-propyl)- piperidin-4-yloxy]-5-fluoro-4-methyl-2H- isoquinolin-1- oneDetermination of Rho Kinase Inhibition

To measure Rho-kinase inhibition, IC₅₀ values were determined accordingto the following protocol:

Active human recombinant ROCK II (N-terminal His6-tagged recombinanthuman ROCK-II residues 11-552) was purchased from Upstate Ltd., Dundee,UK. The peptide substrate, Fluorescein-AKRRRLSSLRA-COOH, was obtainedfrom JPT Peptide Technologies, Berlin, Germany.Adenosine-5′-triphosphate (ATP), bovine serum albumine (BSA),dimethylsulphoxide (DMSO), 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonicacid (Hepes), Brij-35 and dithiothreitol (DTT) were purchased fromSigma-Aldrich, Munich, Germany. Tris(hydroxymethyl)-aminomethane (Tris),magnesium chloride, NaOH, 1M HCl and EDTA were obtained from MerckBiosciences, Darmstadt, Germany. “Complete” protease inhibitor was fromRoche Diagnostics, Mannheim, Germany.

Test compounds were diluted to the appropriate concentrations in buffer1 (25 mM Tris-HCl, pH 7.4, 5 mM MgCl₂, 2 mM DTT, 0.02% (w/v) BSA and 3%DMSO). The ROCK II enzyme was diluted to a concentration of 100 ng/ml inbuffer 2 (25 mM Tris-HCl, pH 7.4, 5 mM MgCl₂, 2 mM DTT and 0.02% (w/v)BSA). The peptide substrate and ATP were diluted to concentrations of 3μM and 120 μM, respectively, in the buffer 2. Two μl of the compoundsolution were mixed with 2 μl of the diluted enzyme in a 384-well smallvolume microtiter plate (Greiner, Bio-One, Frickenhausen, Germany), andthe kinase reaction was initiated by addition of 2 μl of the solutioncontaining peptide substrate and ATP. After 60 min incubation at 32° C.,the reaction was stopped by addition of 20 μl of a solution containing100 mM Hepes-NaOH, pH 7.4, 0.015° A) (v/v) Brij-35, 45 mM EDTA and0.227% chip coating reagent 1 (Caliper Lifescience Inc, Hopkinton,Mass.). Phosphorylation of the substrate peptide was then detected on aCaliper 3000 instrument essentially as described by Pommereau et al (J.Biomol. Screening 9(5), 409-416, 2004). Separation conditions were asfollows: Pressure −1.3 psi, upstream voltage −1562 V, downstream voltage−500 V, sample sip time 200 ms. Positive controls (buffer 1 instead ofcompound) and negative controls (buffer 1 instead of compound and buffer2 instead of ROCK II) were run in parallel on each plate.

The following products/compounds were tested in said assay by using therespective form (salt or free base) obtained as in the examplesdescribed above and the following activities were measured.

Example No. pIC50 15 +++++ 11 +++++ 16 +++++ 19 ++++ 22 +++++ 24 +++++55 +++++ 46 +++++ 58 +++++ 66 +++++ 67 ++++ 68 +++++ 69 +++++ 70 +++++75 ++++

The given activity is denoted as the negative decadal logarithm of theIC₅₀ (pIC₅₀) as follows:

+: pIC50≦3.0

++: 3.0≦pIC₅₀<4.0

+++4.0≦pIC₅₀<5.0

++++: 5.0≦pIC₅₀<6.0

+++++: 6.0≦pIC₅₀

The invention claimed is:
 1. A method for the treatment in a mammal of adisease associated with Rho-kinase and/or Rho-kinase mediatedphosphorylation of myosin light chain phosphatase comprisingadministering to the mammal in need thereof at least one compound of theformula (I)

wherein R₁ is OH; R₂ is H, halogen or (C₁-C₆)alkyl; R₃ is H, halogen,(C₁-C₆)alkyl, (C₁-C₆)alkylene-R′, OH, O—R″, NH₂, NHR″, NR″R″ orNH—C(O)—R″, R₄ is H, halogen, hydroxy, CN, (C₁-C₆)alkyl, R′,(C₁-C₆)alkylene-R′; R₅ is H, halogen, CN, NO₂, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, R′, (C₁-C₆)alkylene-(C₆-C₁₀)aryl,(C₂-C₆)alkenylene-(C₆-C₁₀)aryl, (C₁-C₆)alkylene-(C₅-C₁₀)heterocyclyl,CH(OH)—(C₁-C₆)alkyl, NH₂, NH—R′, NH—SO₂H, NH—SO₂—(C₁-C₆)alkyl,NH—SO₂—R′, NH—C(O)—(C₁-C₆)alkyl, NH—C(O)—R′, C(O)N[(C₁-C₆)alkyl]₂,C(O)OH, or C(O)O—(C₁-C₆)alkyl; R₆ is(C₁-C₆)alkylene-C(O)NH—(C₁-C₆)alkyl,(C₁-C₆)alkylene-C(O)N[(C₁-C₆)alkyl]₂,(C₁-C₆)alkylene-C(O)O—(C₁-C₆)alkyl, C(O)(C₁-C₆)alkyl, C(O)R′,C(O)—(C₁-C₆)alkylene-R′; R₇ is H, Halogen, CN, NO₂, (C₁-C₆)alkyl,O—(C₁-C₆)alkyl, (C₂-C₆)alkenyl, R′, (C₂-C₆)alkenylene-(C₆-C₁₀)aryl,(C₁-C₆)alkylene-R′, CH(OH)—(C₁-C₆)alkyl, NH₂, NH—R′, NH—SO₂H,NH—SO₂—(C₁-C₆)alkyl, NH—SO₂—R′, SO₂—NH₂, SO₂—NHR′, NH—C(O)—(C₁-C₆)alkyl,NH—C(O)—R′, C(O)N[(C₁-C₆)alkyl]₂, C(O)OH, or C(O)O—(C₁-C₆)alkyl; R₈ isH, halogen or (C₁-C₆)alkyl; n is 1, 2, 3 or 4; m is 1, 2, 3, 4 or 5; andL is O or O—(C₁-C₆)alkylene; wherein R′ is (C₃-C₈)cycloalkyl,(C₅-C₁₀)heterocyclyl, (C₆-C₁₀)aryl; R″ is (C₃-C₈)cycloalkyl,(C₅-C₁₀)heterocyclyl, (C₆-C₁₀)aryl, (C₁-C₆)alkyl, (C₁-C₆)alkylene-R′,(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, (C₁-C₆)alkylene-O—R′, or(C₁-C₆)alkylene-NR_(x)R_(y); and wherein R_(x) and R_(y) areindependently of each other (C₁-C₆)alkyl, (C₅-C₁₀)heterocyclyl,(C₆-C₁₀)aryl, (C₁-C₄)alkylene-(C₅-C₁₀)heterocyclyl,(C₁-C₄)alkylene-(C₆-C₁₀)aryl, (C₁-C₄)alkylene-NH(C₁-C₆)alkyl,(C₁-C₄)alkylene-N[(C₁-C₆)alkyl]₂, (C₁-C₄)alkylene-N[(C₆-C₁₀)aryl]₂, or(C₁-C₄)alkylene-N[(C₅-C₁₀)heterocyclyl]₂; wherein in residues R₄, R₅,R₆, R₇ and R₈ alkyl, alkylene or cycloalkyl can optionally besubstituted one or more times by OH, OCH₃, COOH, COOCH₃, NH₂, NHCH₃,N(CH₃)₂, CONHCH₃ or CON(CH₃)₂; wherein in residues R₂ to R₈ alkyl oralkylene can optionally be substituted one or more times by halogen;wherein in residues R₃ to R₈ (C₆-C₁₀)aryl and (C₅-C₁₀)heterocyclyl areunsubstituted or substituted one or more times by suitable groupsindependently selected from halogen, OH, NO₂, N₃, CN, C(O)—(C₁-C₆)alkyl,C(O)—(C₆-C₁₀)aryl, COOH, COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₆)alkyl,CON[(C₁-C₆)alkyl]₂, (C₃-C₈)cycloalkyl, (C₁-C₆)alkyl, (C₁-C₆)alkylene-OH,(C₁-C₆)alkylene-NH₂, (C₁-C₆)alkylene-NH(C₁-C₆)alkyl,(C₁-C₆)alkylene-N[(C₁-C₆)alkyl]₂, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,O—(C₁-C₆)alkyl, O—C(O)—(C₁-C₆)alkyl, PO₃H₂, SO₃H, SO₂—NH₂,SO₂NH(C₁-C₆)alkyl, SO₂N[(C₁-C₆)alkyl]₂, S—(C₁-C₆)alkyl; SO—(C₁-C₆)alkyl,SO₂—(C₁-C₆)alkyl, SO₂—N═CH—N[(C₁-C₆)alkyl]₂, C(NH)(NH₂), NH₂,NH—(C₁-C₆)alkyl, N[(C₁-C₆)alkyl]₂, NH—C(O)—(C₁-C₆)alkyl,NH—C(O)O—(C₁-C₆)alkyl, NH—SO₂—(C₁-C₆)alkyl, NH—SO₂—(C₆-C₁₀)aryl,NH—SO₂—(C₅-C₁₀)heterocyclyl, N(C₁-C₆)alkyl-C(O)—(C₁-C₆)alkyl,N(C₁-C₆)alkyl-C(O)O—(C₁-C₆)alkyl, N(C₁-C₆)alkyl-C(O)—NH—(C₁-C₆)alkyl],(C₆-C₁₀)aryl, (C₁-C₆)alkylene-(C₆-C₁₀)aryl, O—(C₆-C₁₀)aryl,O—(C₁-C₆)alkylene-(C₆-C₁₀)aryl, (C₅-C₁₀)heterocyclyl,(C₁-C₆)alkylene-(C₅-C₁₀)heterocyclyl, orO—(C₁-C₆)alkylene-(C₅-C₁₀)heterocyclyl, wherein the (C₆-C₁₀)aryl or(C₅-C₁₀)heterocyclyl may be substituted one to three times by a groupindependently selected from halogen, OH, NO₂, CN, O—(C₁-C₆)alkyl,(C₁-C₆)alkyl, NH₂, NH(C₁-C₆)alkyl, N[(C₁-C₆)alkyl]₂, SO₂CH₃, COOH,C(O)O—(C₁-C₆)alkyl, CONH₂, (C₁-C₆)alkylene-O—(C₁-C₆)alkyl,(C₁-C₆)alkylene-O—(C₆-C₁₀)aryl, or O—(C₁-C₆)alkylene-(C₆-C₁₀)aryl; orwherein (C₆-C₁₀)aryl is vicinally substituted by a O—(C₁-C₄)alkylene-Ogroup whereby a 5-8-membered ring is formed together with the carbonatoms the oxygen atoms are attached to; and wherein aryl or heterocyclylsubstituents of (C₆-C₁₀)aryl and (C₅-C₁₀)heterocyclyl groups may not befurther substituted by an aryl or heterocyclyl containing group; ortheir stereoisomeric and/or tautomeric forms and/or theirpharmaceutically acceptable salts.
 2. The method according to claim 1,wherein the disease is selected from the group consisting ofhypertension, pulmonary hypertension, ocular hypertension, retinopathy,glaucoma, peripheral circulatory disorder, peripheral arterial occlusivedisease (PAOD), coronary heart disease, angina pectoris, hearthypertrophy, heart failure, ischemic diseases, ischemic organ failure,thrombotic disorders, stroke, cerebral vasospasm, cerebral ischemia,Alzheimer's disease, arteriosclerosis, blood vessel restenosis, oratherosclerosis.
 3. The method according to claim 1 wherein the compoundof formula (I) is characterized by the formula (III)


4. The method according to claim 1 wherein the compound of formula (I)is characterized by the formula (III′)


5. The method according to claim 1 wherein in formula (I) R₃ is H,halogen, (C₁-C₄)alkylene-R′, O—R″ or NHR″.
 6. The method according toclaim 1 wherein in formula (I) R₈ is H, halogen or (C₁-C₄)alkyl.
 7. Themethod according to claim 1 wherein in formula (I) R₄ is H, halogen or(C₁-C₆)alkyl.
 8. The method according to claim 1 wherein in formula (I)R₅ is H, halogen, CN, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, R′, NH—(C₆-C₁₀)aryl,(C₁-C₆)alkylene-(C₆-C₁₀)aryl or (C₁-C₆)alkylene-(C₅-C₁₀)heterocyclyl. 9.The method according to claim 1 wherein in formula (I) R₇ is H, halogen,CN, (C₁-C₆)alkyl, O—(C₁-C₆)alkyl, (C₂-C₆)alkenyl, R′ or(C₁-C₆)alkylene-(C₃-C₈)cycloalkyl.
 10. The method according to claim 1wherein in formula (I) m is 2, 3, or
 4. 11. The method according toclaim 1 wherein in formula (I) m is
 3. 12. The method according to claim1 wherein in formula (I) R₂ is H, halogen, or (C₁-C₄)alkyl.
 13. Themethod according to claim 1 wherein in formula (I) n is 1, 2 or
 3. 14.The method according to claim 1 wherein in formula (I) R₆ is(C₁-C₆)alkylene-C(O)N[(C₁-C₆)alkyl]₂,(C₁-C₆)alkylene-C(O)NH—(C₁-C₆)alkyl, (C₁-C₆)alkylene-C(O)O—(C₁-C₆)alkyl,C(O)(C₁-C₆)alkyl, C(O)(C₅-C₁₀)heterocyclyl, C(O)(C₃-C₈)cycloalkylC(O)(C₁-C₆)alkylene-(C₃-C₈)cycloalkyl,C(O)(C₁-C₆)alkylene-C₅-C₁₀)heterocyclyl, orC(O)(C₁-C₆)alkylene-(C₆-C₁₀)aryl.
 15. The method according to claim 1wherein in formula (I) R₆ is C(O)(C₁-C₆)alkyl, C(O)(C₃-C₈)cycloalkyl,C(O)—(C₅-C₁₀)heterocyclyl, C(O)(C₁-C₄)alkylene-(C₅-C₁₀)heterocyclyl, orC(O)(C₁-C₄)alkylene-(C₆-C₁₀)aryl.
 16. The method according to claim 1wherein in formula (I) R₆ is C(O)(C₁-C₆)alkyl; C(O)(C₃-C₆)cycloalkyl;C(O)—(C₅-C₆)heterocyclyl wherein the heterocyclyl is unsubstituted;C(O)(C₁-C₄)alkylene-(C₅-C₁₀)heterocyclyl wherein the heterocyclyl isunsubstituted; or C(O)(C₁-C₄)alkylene-(C₆-C₁₀)aryl wherein the aryl isunsubstituted or substituted one or more times by halogen; and wherein a(C₁-C₄)alkyl or (C₁-C₆)alkyl residue is unsubstituted or substituted oneto three times by a group independently selected from halogen, OH, NH₂,NH(CH₃) or N(CH₃)₂, a (C₁-C₄)alkylene residue is unsubstituted orsubstituted once by amino or N(CH₃)₂ and a (C₃-C₈)cycloalkyl residue isunsubstituted or substituted once by NH₂.
 17. The method according toclaim 1 wherein in formula (I) m is 3 and L is attached to the3-position or to the 4-position of the piperidine ring.
 18. The methodaccording to claim 1 wherein in formula (I) L is O-methylene,O-ethylene, or O.
 19. The method according to claim 1 wherein in formula(I) R₁ is OH; R₂ is hydrogen, halogen, or (C₁-C₆)alkyl; R₃ is H,halogen, (C₁-C₄)alkylene-R′, O—R″ or NHR″; R₄ is H, halogen or(C₁-C₆)alkyl; R₅ is H, (C₁-C₆)alkyl, halogen, CN, (C₂-C₆)alkenyl,(C₆-C₁₀)aryl, NH—(C₆-C₁₀)aryl, (C₁-C₆)alkylene-(C₆-C₁₀)aryl,(C₅-C₁₀)heterocyclyl or (C₁-C₆)alkylene-(C₅-C₁₀)heterocyclyl; R₆ is,(C₁-C₆)alkylene-C(O)N[(C₁-C₄)alkyl]₂, C(O)(C₁-C₆)alkyl,C(O)(C₃-C₈)cycloalkyl, C(O)—(C₁-C₆)alkylene-C₃-C₈)cycloalkyl,C(O)(C₁-C₆)alkylene-C₅-C₁₀)heterocyclyl, orC(O)—(C₁-C₆)alkylene-(C₆-C₁₀)aryl; R₇ is H, halogen, CN, (C₁-C₆)alkyl,O—(C₁-C₆)alkyl, (C₂-C₆)alkenyl or R′; R₈ is H, halogen or (C₁-C₆)alkyl;m is 2, 3 or 4 n is 1, 2 or 3, and L is O,O-methylene or O-ethylene. 20.The method according to claim 1 wherein in formula (I) R₁ is OH; R₂ is Hor (C₁-C₄)alkyl; R₃ is H, halogen or NHR″, wherein R″ is defined asabove; R₄ is H, halogen or (C₁-C₄)alkyl; R₅ is H, (C₁-C₆)alkyl, halogen,(C₂-C₄)alkenyl, (C₆-C₁₀)aryl, (C₁-C₆)alkylene-(C₆-C₁₀)aryl or(C₅-C₁₀)heterocyclyl; R₆ is C(O)(C₁-C₆)alkyl, C(O)(C₃-C₈)cycloalkyl,C(O)—(C₅-C₁₀)heterocyclyl, C(O)(C₁-C₆)alkylene-(C₃-C₈)cycloalkyl,C(O)(C₁-C₆)alkylene-(C₅-C₁₀)heterocyclyl, orC(O)(C₁-C₆)alkylene-(C₆-C₁₀)aryl; R₇ is H, halogen, CN, (C₁-C₆)alkyl,O(C₁-C₆)alkyl, (C₂-C₆)alkenyl or R′; R₈ is H, halogen or (C₁-C₆)alkyl; mis 2, 3 or 4 n is 1, 2 or 3; and L is O.